Cyclic urea derivatives, pharmaceutical compositions containing these compounds and processes for preparing them

ABSTRACT

The invention relates to cyclic urea derivatives of general formula ##STR1## wherein R a , R b , X and Y are as defined herein, pharmaceutical compositions containing the derivatives and processes for preparing them.

This is a division of application Ser. No. 08/144,909, filed Oct. 28,1993, U.S. Pat. No. 5,478,942 which is a division of application Ser.No. 07/849,557, filed Mar. 11, 1992 U.S. Pat. No. 5,276,049.

The invention relates to cyclic urea derivatives of general formula##STR2## the tautomers and stereoisomers thereof, including the mixturesand the addition salts thereof, particularly the physiologicallyacceptable addition salts with inorganic or organic acids or bases whichhave, inter alia, valuable pharmacological properties, preferablyaggregation-inhibiting effects, pharmaceutical compositions whichcontain these compounds and processes for preparing them.

In general formula I above

X represents a carbimino group optionally substituted at the nitrogenatom by an alkyl, aralkyl, aryl, heteroaryl or cyano group, or acarbonyl, thiocarbonyl, sulphinyl or sulphonyl group,

Y represents a straight-chained C₂₋₄ -alkylene or alkenylene groupoptionally substituted by R_(c) or R_(d) or by R_(c) and R_(d), whereinthe above-mentioned alkylene or alkenylene groups additionally may bemono- or disubstituted by fluorine, chlorine or bromine atoms or byalkyl, trifluoromethyl, aralkyl, aryl, heteroaryl or alkylcarbonylgroups, whilst the substituents may be identical or different and, inaddition, one or two methylene groups may each be replaced by a carbonylgroup, or Y represents a 1,2-cycloalkylene group having 4 to 7 carbonatoms optionally substituted by R_(c) or R_(d) or by R_(c) and R_(d),

or Y represents a 1,2-cycloalkenylene group having 4 to 7 carbon atomsor a 1,2-phenylene group in which one or two methine groups may bereplaced by a nitrogen atom and which may be substituted in the carbonskeleton by a fluorine, chlorine or bromine atom, by a C₁₋₄ -alkylgroup, by a trifluoromethyl, hydroxy, alkoxy, alkylsulphenyl,alkylsulphinyl, alkylsulphonyl, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, carboxy, nitro, (R₁)₂ N--, (R₁)₂ NCO-- or (R₁)₂ NSO₂ --group (wherein the groups R₁ may be identical or different and may eachrepresent a hydrogen atom or an alkyl, aralkyl, aryl or heteroarylgroup), or by a R₁ NH group substituted by an alkylcarbonyl,arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, alkylsulphonyl,aralkylsulphonyl or arylsulphonyl group, and wherein, additionally, oneor two --CH═CH-- groups may each be replaced by a --CO--NR₁ -- group,

or Y represents a --CO--NH--, --NH--CO--, --CH═N-- or --N═CH-- groupoptionally substituted by R_(c) or R_(d),

one of the groups R_(a) to R_(d) represents a group of formula

    A-B-C-

wherein

A represents a straight-chained or branched C₁₋₅ -aminoalkyl group, anamino, amidino or guanidino group, whilst in each of the above-mentionedgroups at one of the nitrogen atoms, one or two hydrogen atoms may bereplaced by a C₁₋₄ -alkyl or one hydrogen atom may be replaced by a C₂₋₅-alkoxycarbonyl group or by an alkylcarbonyl, arylcarbonyl,aryloxycarbonyl or aralkoxycarbonyl group, or A may represent a cyanogroup, a cyanoalkyl group having 1 to 4 carbon atoms in the alkyl moietyor, if A is bound to a nitrogen atom of groups B or C which is not partof a lactam group, it may represent a hydrogen atom or an alkyl group,

B represents a bond,

an alkylene or alkenylene group,

a phenylene group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms, by C₁₋₄ -alkyl groups, by trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, (R₁)₂N--, (R₁)₂ NCO--, (R₁)₂ NSO₂ -- or nitro groups or by R₁ NH groupssubstituted by an alkylcarbonyl, aralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkylsulphonyl, aralkylsulphonyl or arylsulphonylgroup, whilst the substituents may be identical or different,

a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene ortriazinylene group, which may be alkyl-substituted in the carbonskeleton, whilst additionally one or two --CH═N-- groups may be replacedby a --CO--NR₁ -- group and one of the nitrogen atoms, instead of beingbound to the group R₁, may also be bound to the group C, provided thatthe latter is not attached to group B by a heteroatom or a carbonylgroup,

a cyclopropylene group optionally substituted by an alkyl, aralkyl oraryl group,

a C₄₋₅ -cycloalkylene group optionally substituted by an alkyl, aralkylor aryl group, wherein a CH moiety may be replaced by a nitrogen atomand additionally a methylene group adjacent to the nitrogen atom may bereplaced by a carbonyl group,

a C₆₋₇ -cycloalkylene group optionally substituted by an alkyl, aralkylor aryl group, wherein one or two CH moieties in the 1,4-positionrelative to one another may each be replaced by a nitrogen atom, whilstadditionally one or two of the methylene groups adjacent to a nitrogenatom may each be replaced by a carbonyl group,

a biphenylene group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms or by alkyl, trifluoromethyl, hydroxy, alkoxy,alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, alkylcarbonyl-NR₁ -- oralkylsulphonyl-NR₁ -- groups, whilst the substituents may be identicalor different and R₁ is as hereinbefore defined, and

C represents an alkylene or alkenylene group optionally substituted by ahydroxy, alkoxy or (R₁)₂ N-- group,

an alkylenecarbonyl group connected to the group B via the carbonylgroup,

a phenylene group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms, by C₁₋₄ -alkyl groups, by trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, (R₁)₂N--, (R₁)₂ NCO--, (R₁)₂ NSO₂ -- or nitro groups or by R₁ NH-- groupssubstituted by an alkylcarbonyl, aralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkylsulphonyl, aralkylsulphonyl or arylsulphonylgroup, whilst the substituents may be identical or different,

an indanylene or 1,2,3,4-tetrahydronaphthylene group, wherein in eachcase the saturated ring is bound to the group A and the aromatic ring isbound to the cyclic urea skeleton,

a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene ortriazinylene group which may be substituted in the carbon skeleton by analkyl group, whilst additionally one or two --CH═N-- groups may each bereplaced by a --CO--NR₁ -- group and one of the nitrogen atoms, insteadof being bound to the group R₁, may also be bound to the group B,provided that the latter is not a bond or does not adjoin the group Cwith a heteroatom,

a C₄₋₅ -cycloalkylene group optionally substituted by an alkyl, aralkylor aryl group wherein a CH moiety may be replaced by a nitrogen atom andin addition a methylene group adjacent to the nitrogen atom may bereplaced by a carbonyl group, or

a C₆₋₇ -cycloalkylene group optionally substituted by an alkyl, aralkylor aryl group, wherein one or two CH moieties located in the1,4-position relative to each other may each be replaced by a nitrogenatom, whilst additionally one or two of the methylene groups adjacent toa nitrogen atom may each be replaced by a carbonyl group,

a second of the groups R_(a) to R_(d) represents a group of the formula

    F-E-D-

wherein

D represents a C₁₋₅ -alkylene group or a C₂₋₅ -alkenylene group,

a phenylene group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms, by C₁₋₄ -alkyl groups, by trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl,carboxyalkoxy, alkoxycarbonylalkoxy, aralkoxycarbonyl-alkoxy, (R₁)₂ N--,(R₁)₂ NCO--, (R₁)₂ NSO₂ -- or nitro groups or by R1NH-- groupssubstituted by an alkylcarbonyl, aralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkylsulphonyl, aralkylsulphonyl or arylsulphonylgroup, the substituents being identical or different,

a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene ortriazinylene group which may be alkyl-substituted in the carbonskeleton, whilst additionally one or two --CH═N-- groups may each bereplaced by a --CO--NR₁ -- group and one of the nitrogen atoms, insteadof being bound to the group R₁, may also be bound to the group E,provided that the latter is not a bond or is not bound to the group D bymeans of a heteroatom,

a CD₄₋₅ -cycloalkylene group optionally substituted by an alkyl, aralkylor aryl group, wherein a CH moiety may be replaced by a nitrogen atomand in addition a methylene group adjacent to the nitrogen atom may bereplaced by a carbonyl group,

a C₆₋₇ -cycloalkylene group optionally substituted by an alkyl, aralkylor aryl group, wherein one or two CH moieties in the 1,4-positionrelative to each other may each be replaced by a nitrogen atom, whilstadditionally one or two of the methylene groups adjacent to the nitrogenatom may each be replaced by a carbonyl group, or

a C₂₋₆ -alkylene group interrupted by the group W, wherein W representsan oxygen or sulphur atom, a sulphinyl, sulphonyl, R₁ N═,(alkylcarbonyl)N═, (aralkylcarbonyl)N═, (arylcarbonyl)N═,(heteroarylcarbonyl)N═, (alkylsulphonyl)N═, (arylsulphonyl)N═,aminocarbonyl or carbonylamino group,

E represents a bond,

a C₁₋₅ -alkylene group or a C₂₋₅ -alkenylene group, each of which may besubstituted by one or two alkyl groups, or by a hydroxy, alkoxy, amino,alkylamino, aralkylamino, dialkylamino, bis(aralkyl)amino, carboxyalkyl,alkoxycarbonylalkyl or aralkoxycarbonylalkyl group,

a phenylene group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms, by C₁₋₄ -alkyl groups, by trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, (R₁)₂N--, (R₁)₂ NCO--, (R₁)₂ NSO₂ -- or nitro groups or by R₁ NH-- groupssubstituted by an alkylcarbonyl, aralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkylsulphonyl, aralkylsulphonyl or arylsulphonylgroup, the substituents being identical or different,

a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene ortriazinylene group which may be alkyl-substituted in the carbonskeleton, whilst additionally one or two --CH═N-- groups may each bereplaced by a --CO--NR₁ -- group and one of the nitrogen atoms, insteadof being bound to the group R₁, may also be bound to the group D,

a C₄₋₅ -cycloalkylene group optionally substituted by an alkyl, aralkylor aryl group, wherein a CH moiety may be replaced by a nitrogen atomand in addition a methylene group adjacent to the nitrogen atom may bereplaced by a carbonyl group,

a C₆₋₇ -cycloalkylene group optionally substituted by an alkyl, aralkylor aryl group, wherein one or two CH moieties in the 1,4-positionrelative to each other may each be replaced by a nitrogen atom, whilstadditionally one or two of the methylene groups adjacent to a nitrogenatom may each be replaced by a carbonyl group,

an alkylenearylene group linked to the group D via the aryl moiety or

an alkylene group linked to the group D via the group W, where W is ashereinbefore defined, and

F represents a carbonyl group substituted by a hydroxy or C₁₋₆ -alkoxygroup, whilst a C₁₋₃ -alkoxy group may be substituted in the 1-, 2- or3-position by an aryl or heteroaryl group or in the 2- or 3-position bya pyrrolidin-2-on-1-yl, morpholino, thiomorpholino or1-oxido-thiomorpholino group, or F may represent a sulpho, phosphono,O-alkylphosphono or tetrazol-5-yl group, whilst if A represents a cyanogroup or an amino or aminoalkyl group optionally benzoylated orbenzyloxy-carbonylated at the nitrogen atom, the shortest spacingbetween the nitrogen atom of these groups and group F is at least 10bonds,

the third of the groups R_(a) to R_(d) represents a hydrogen atom, analkyl, perfluoroalkyl, aralkyl, aryl or heteroaryl group or, if thethird of the groups R_(a) to R_(d) is connected to an unsaturated carbonatom of group Y, it may represent an alkoxy, alkylsulphenyl or (R₁)₂ N--group, and

the fourth of the groups R_(a) to R_(d) represents a hydrogen atom, analkyl, aralkyl, aryl or heteroaryl group,

or R_(a) or R_(b) together with an adjacent group R_(c) or R_(d) mayalso represent a bond,

and, unless otherwise specified,

the above-mentioned alkyl, alkylene, alkenylene or alkoxy moieties mayeach contain 1 to 3 carbon atoms, and

the term "an aryl group" used above denotes a phenyl group which may bemonosubstituted by a trifluoromethyl, carboxy, (R₁)₂ NCO--,alkoxycarbonyl, alkylcarbonyl, alkylsulphenyl, alkylsulphinyl,alkylsulphonyl, nitro, (R₁)₂ N--, alkylcarbonyl-NR₁ --,aralkylcarbonyl-NR₁ --, arylcarbonyl-NR₁ --, heteroarylcarbonyl--NR₁ --,alkylsulphonyl-NR₁ --, aralkylsulphonyl-NR₁ --, arylsulphonyl-NR₁ -- or(R₁)₂ N-sulphonyl group or may be mono-, di- or trisubstituted byfluorine, chlorine or bromine atoms or by hydroxy, alkoxy or alkylgroups having 1 to 4 carbon atoms, and

the term "a heteroaryl group" used above denotes a 5-memberedheteroaromatic ring which contains an oxygen, sulphur or nitrogen atom,a nitrogen atom and an oxygen, sulphur or nitrogen atom or two nitrogenatoms and an oxygen, sulphur or nitrogen atom or a 6-memberedheteroaromatic ring which contains one, two or three nitrogen atoms andin which, additionally, one or two --CH═N-- groups may each be replacedby a --CO--NR₁ -- group, whilst the above-mentioned heteroaromatic ringsmay additionally be substituted by one or two alkyl groups or by afluorine, chlorine or bromine atom or by a hydroxy or alkoxy group.

Preferred compounds of general formula I above are those wherein

X represents a carbimino group optionally substituted at the nitrogenatom by an alkyl, aralkyl, aryl, heteroaryl or cyano group, or acarbonyl, thiocarbonyl, sulphinyl or sulphonyl group,

Y represents a straight-chained C₂₋₃ -alkylene or alkenylene groupoptionally substituted by R_(c) or R_(d) or by R_(c) and R_(d), whichmay be mono- or disubstituted by fluorine, chlorine or bromine atoms orby alkyl, trifluoromethyl, aralkyl, aryl, heteroaryl or alkylcarbonylgroups, whilst the substituents may be identical or different and, inaddition, one or two methylene groups may each be replaced by a carbonylgroup, or Y represents a 1,2-cyclohexylene group optionally substitutedby R_(c) or R_(d) or by R_(c) and R_(d),

or Y represents a 1,2-cyclohexenylene group or a 1,2-phenylene groupwherein one or two CH groups may each be replaced by a nitrogen atom andwhich may be substituted in the carbon skeleton by a fluorine, chlorineor bromine atom, by a C₁₋₄ -alkyl group, by a trifluoromethyl, hydroxy,alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, carboxy, nitro, (R₁)₂ N--, (R₁)₂ NCO-- or(R₁)₂ NSO₂ -- group (wherein the groups R₁ may be identical or differentand may each represent a hydrogen atom, an alkyl, aralkyl, aryl orheteroaryl group), or by a R₁ NH-- group substituted by analkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl,alkylsulphonyl, aralkylsulphonyl or arylsulphonyl group, and wherein,additionally, one or two --CH═CH-- groups may each be replaced by a--CO--NR₁ -- group,

a --CO--NH--, --NH--CO--, --CH═N-- or --N═CH-- group optionallysubstituted by R_(c) or R_(d),

one of the groups R_(a) to R_(d) represents a group of the formula

    A-B-C-

wherein

A represents a straight-chained or branched C₁₋₅ -aminoalkyl group, anamino, amidino or guanidino group, whilst in each of the above-mentionedgroups, at one of the nitrogen atoms, one or two hydrogen atoms may bereplaced by a C₁₋₄ -alkyl group or a hydrogen atom may be replaced by aC₂₋₅ -alkoxycarbonyl group, by an alkylcarbonyl, arylcarbonyl,aryloxycarbonyl or aralkoxycarbonyl group, or A represents a cyanogroup, a cyanoalkyl group having 1 to 4 carbon atoms in the alkyl moietyor, if A is bound to a nitrogen atom of groups B or C which is not partof a lactam group, it may also represent a hydrogen atom or an alkylgroup,

B represents a bond,

an alkylene or alkenylene group,

a phenylene group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms, by C₁₋₄ -alkyl groups, by trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, (R₁)₂N--, (R₁)₂ NCO--, (R₁)₂ NSO₂ -- or nitro groups or by R₁ NH-- groupssubstituted by an alkylcarbonyl, aralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkylsulphonyl, aralkylsulphonyl or arylsulphonylgroup, whilst the substituents may be identical or different,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene groupwhich may be substituted in the carbon skeleton by an alkyl group,whilst additionally one or two --CH═N-- groups may each be replaced by a--CO--NR₁ -- group and one of the nitrogen atoms, instead of being boundto the group R1, may also be bound to the group C, provided that thelatter does not adjoin the group B with a heteroatom or a carbonylgroup,

a C₃₋₅ -cycloalkylene group,

a cyclohexylene group wherein one or two CH moieties in the 1,4-positionrelative to each other may be replaced by nitrogen atoms, whilstadditionally one or two of the methylene groups adjacent to a nitrogenatom may each be replaced by a carbonyl group, or

a biphenylene group and

C represents an alkylene or alkenylene group optionally substituted by ahydroxy group,

an alkylenecarbonyl group connected to the group B via the carbonylgroup,

a phenylene group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms, by C₁₋₄ -alkyl groups, by trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, (R₁)₂N--, (R₁)₂ NCO--, (R₁)₂ NSO₂ -- or nitro groups or by R₁ NH-- groupssubstituted by an alkylcarbonyl, aralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkylsulphonyl, aralkylsulphonyl or arylsulphonylgroup, the substituents being identical or different,

an indanylene or 1,2,3,4-tetrahydronaphthylene group wherein, in eachcase, the saturated ring is bound to the group A and the aromatic ringis bound to the cyclic urea skeleton,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group,each of which may be substituted in the carbon skeleton by an alkylgroup, whilst additionally one or two --CH═N-- groups may each bereplaced by a --CO--NR₁ -- group and one of the nitrogen atoms, insteadof being bound to the group R₁, may also be bound to the group B,provided that the latter does not represent a bond or is not adjacent tothe group C with a heteroatom,

a cyclohexylene group wherein one or two CH moieties in the 1,4-positionrelative to each other may be replacd by nitrogen atoms, whilstadditionally one or two of the methylene groups adjacent to a nitrogenatom may each be replaced by a carbonyl group and the nitrogen atoms maynot be bound to a nitrogen atom of the cyclic urea,

a second of the groups R_(a) to R_(d) represents a group of the formula

    F-E-D-

wherein

D represents a C₁₋₅ -alkylene group or a C₂₋₅ -alkenylene group,

a phenylene group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms, by C₁₋₄ -alkyl groups, by trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl,carboxyalkoxy, alkoxycarbonylalkoxy, aralkoxycarbonyl-alkoxy, (R₁)₂ N--,(R₁)₂ NCO--, (R₁)₂ NSO₂ -- or nitro groups or by R₁ NH-- groupssubstituted by an alkylcarbonyl, aralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkylsulphonyl, aralkylsulphonyl or arylsulphonylgroup, the substituents being identical or different,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group,each of which may be substituted by an alkyl group in the carbonskeleton, whilst additionally one or two --CH═N-- groups may each bereplaced by a --CO--NR₁ -- group and one of the nitrogen atoms insteadof being bound to the group R₁ may also be bound to the group E,provided that the latter does not represent a bond or is not bound by aheteroatom to the group D,

a cyclohexylene group wherein one or two CH moieties in the 1,4-positionrelative to each other may be replaced by nitrogen atoms, whilstadditionally one or two of the methylene groups adjacent to a nitrogenatom may each be replaced by a carbonyl group, or

a C₃₋₆ -alkylene group interrupted by the group W, wherein W representsan oxygen or sulphur atom, a sulphinyl, sulphonyl, R₁ N═,(alkylcarbonyl)N═, (aralkylcarbonyl)N═, (arylcarbonyl)N═,(heteroarylcarbonyl)N═, (alkylsulphonyl)N═ or (arylsulphonyl)N═ groupand the alkylene group linked to a nitrogen atom of the cyclic ureacontains 2 or 3 carbon atoms,

E represents a bond,

a C₁₋₅ -alkylene group or a C₂₋₅ -alkenylene group, each of which may besubstituted by one or two alkyl groups, by a hydroxy, alkoxy, amino,alkylamino, aralkylamino, dialkylamino, bis(aralkyl)amino, carboxyalkyl,alkoxycarbonylalkyl or aralkoxycarbonylalkyl group,

a phenylene group which may be mono- or disubstituted by fluorine,chlorine or bromine atoms, by C₁₋₄ -alkyl groups, by trifluoromethyl,hydroxy, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, (R₁)₂N--, (R₁)₂ NCO--, (R₁)₂ NSO₂ -- or nitro groups or by R₁ --NH-- groupssubstituted by an alkylcarbonyl, aralkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkylsulphonyl, aralkylsulphonyl or arylsulphonylgroup, whilst the substituents may be identical or different,

a pyridinylene, pyrimidinylene, pyrazinylene or pyridazinylene group,each of which may be alkyl-substituted in the carbon skeleton, whilstadditionally one or two --CH═N-- groups may each be replaced by a--CO--NR₁ -- group and one of the nitrogen atoms, instead of being boundto the group R₁, may also be bound to the group D,

a cyclohexylene group wherein one or two CH moieties in the 1,4-positionrelative to each other may be replaced by nitrogen atoms, whilstadditionally one or two of the methylene groups adjacent to a nitrogenatom may each be replaced by a carbonyl group,

an alkylenearylene group linked to the group D via the aryl group or

an alkylene group linked to the group D via the group W', wherein W'represents an oxygen or sulphur atom, a sulphinyl, sulphonyl, R₁ N═,(alkycarbonyl)N═, (aralkylcarbonyl)N═, (arylcarbonyl)N═,(heteroaryl-carbonyl)N═, (alkylsulphonyl)N═, (arylsulphonyl)N═ oraminocarbonyl group wherein the nitrogen atom is bound to the alkylenegroup,

F represents a carbonyl group which is substituted by a hydroxy or C₁₋₆-alkoxy group, whilst a C₁₋₃ -alkoxy group may be substituted in the 1-,2- or 3-position by an aryl or heteroaryl group or in the 2- or3-position by a pyrrolidin-2-on-1-yl, morpholino, thiomorpholino or1-oxido-thiomorpholino group, or F may represent a sulpho, phosphono,O-alkylphosphono or tetrazol-5-yl group, whilst if A represents a cyanogroup or an amino or aminoalkyl group optionally benzoylated orbenzyloxy-carbonylated at the nitrogen atom, the shortest distancebetween the nitrogen atom of these groups and the group F being at least10 bonds,

the third of the groups R_(a) to R_(d) is a hydrogen atom, an alkyl,trifluoromethyl, aralkyl, aryl or heteroaryl group or, if the third ofthe groups R_(a) to R_(d) is bound to an unsaturated carbon atom ofgroup Y, it may represent an alkoxy, alkylsulphenyl or (R₁)₂ N-- groupand

the fourth of groups R_(a) to R_(d) represents a hydrogen atom or analkyl, aralkyl, aryl or heteroaryl group,

particularly those compounds of general formula I

wherein

X represents a carbimino group optionally substituted at the nitrogenatom by a methyl, phenyl or pyridyl group, or represents a carbonyl,thiocarbonyl or sulphonyl group,

Y represents a straight-chained alkylene or alkenylene group, eachhaving 2 or 3 carbon atoms, optionally substituted by R_(c) or R_(d) orby R_(c) and R_(d), which may be substituted by a chlorine atom, by oneor two methyl groups or by a trifluoromethyl, phenyl or acetyl group,whilst additionally a methylene group may be replaced by a carbonylgroup,

or Y represents a --CO--NH--, --NH--CO--, --CH═N-- or --N═CH-- group,optionally substituted by R_(c) or R_(d), or a 1,2-phenylene or2,3-pyridinylene group,

one of the groups R_(a) to R_(d) represents a group of formula

    A-B-C-

wherein

A represents a straight-chained or branched C₁₋₄ -aminoalkyl group, anamino, amidino or guanidino group, whilst in each of the above-mentionedgroups, at one of the nitrogen atoms, one or two hydrogen atoms may eachbe replaced by a C₁₋₄ -alkyl group or a hydrogen atom may be replaced byan alkoxycarbonyl group having a total of 2 to 5 carbon atoms or by abenzyloxycarbonyl group, or, if A is bound to a nitrogen atom of group Cwhich is not part of a lactam group, it may represent a hydrogen atom,

B represents a bond,

a phenylene group which may be substituted by one or two methyl groups,by a fluorine, chlorine or bromine atom, by a methoxy, methylsulphenyl,methylsulphinyl, methylsulphonyl, nitro, amino, acetylamino,benzoylamino or methanesulphonylamino group,

a C₃₋₆ -cycloalkylene group,

a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene orbiphenylene group,

C represents an ethylene group optionally substituted by a hydroxygroup,

a methylenecarbonyl group linked to the group B via the carbonyl group,

a phenylene group which may be substituted by one or two methyl groups,by a fluorine, chlorine or bromine atom, by a methoxy, methylsulphenyl,methylsulphinyl, methylsulphonyl, nitro, amino, acetylamino,benzoylamino or methanesulphonylamino group,

an indanylene or 1,2,3,4-tetrahydronaphthylene group wherein thesaturated ring is bound to the group A and the aromatic ring is bound tothe cyclic urea skeleton,

a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene,cyclohexylene or piperidinylene group, wherein the nitrogen atom may notbe bound to a nitrogen atom of the cyclic urea,

a second of groups R_(a) to R_(d) represents a group of formula

    F-E-D-

wherein D represents a C₁₋₄ -alkylene group,

a phenylene group which may be substituted by a fluorine, chlorine orbromine atom, by a methyl, methoxy, methylsulphenyl, methylsulphinyl,methylsulphonyl, carboxymethoxy, methoxycarbonyl-methoxy, nitro, amino,acetylamino, benzoylamino or methanesulphonylamino group,

a pyridinylene, cyclohexylene or piperidinylene group, whilstadditionally in a pyridinylene group a --CH═N-- group may be replaced bya --CO--NH-- group, whilst the nitrogen atom, instead of being bound tothe hydrogen atom, may also be bound to the group E, provided that thelatter is not a bond or is not bound by a heteroatom to group D, or

a C₃₋₅ -alkylene group interrupted by the group W, wherein W representsan oxygen or sulphur atom, a sulphinyl, sulphonyl, imino, methylimino,acetylimino, benzoylimino or methanesulphonylimino group and thealkylene group linked to the cyclic urea contains 2 or 3 carbon atoms,

E represents a bond,

a C₁₋₃ -alkylene group optionally substituted by one or two methylgroups or by a hydroxy, methoxy, amino, dimethylamino, dibenzylamino,carboxymethyl or methoxycarbonylmethyl group or a C₂₋₃ -alkenylenegroup,

a phenylene group or

a C₁₋₂ -alkylene group linked to group D by the group W', wherein W'represents an oxygen or sulphur atom or a sulphinyl, sulphonyl oraminocarbonyl group, the amino group being bound to the alkylene group,and

F represents a carbonyl group which is substituted by a hydroxy group,by a C₁₋₄ -alkoxy group or by a phenylalkoxy group having 1 or 2 carbonatoms in the alkoxy moiety, or F represents a phosphono,O-methylphosphono or tetrazol-5-yl group, whilst if A represents anamino or aminoalkyl group optionally benzyloxycarbonylated at thenitrogen atom, the shortest distance between the nitrogen atom of thisgroup and group F is at least 10 bonds,

the third of the groups R_(a) to R_(d) represents a hydrogen atom, amethyl, ethyl, trifluoromethyl or phenyl group and

the fourth of groups R_(a) to R_(d) represents a hydrogen atom or amethyl group,

the tautomers, the stereoisomers, including the mixtures thereof, andthe addition salts thereof.

Particularly preferred compounds of general formula I are those wherein

X represents a carbonyl or sulphonyl group,

Y represents a straight-chained alkylene or alkenylene group each having2 or 3 carbon atoms, optionally substituted by R_(c) or R_(d) or byR_(c) and R_(d), which may be substituted by one or two methyl groups orby a trifluoromethyl or phenyl group, whilst additionally a methylenegroup may be replaced by a carbonyl group, or Y represents an --N═CH--or --CH═N-- group optionally substituted by R_(c) or R_(d),

one of the groups R_(a) to R_(d) represents a group of the formula

    A-B-C-

wherein

A represents a straight-chained or branched C₁₋₄ -aminoalkyl group, anamino or amidino group, whilst in each of the above-mentioned groups, atone of the nitrogen atoms, a hydrogen atom may be replaced by analkoxycarbonyl group having a total of 2 to 5 carbon atoms or by abenzyloxycarbonyl group,

B represents a bond,

a phenylene group which may be substituted by a fluorine or chlorineatom,

a cyclopropylene, pyridinylene, pyrimidinylene, pyrazinylene orpyridazinylene group,

C represents a phenylene group which may be substituted by one or twomethyl groups, by a fluorine, chlorine or bromine atom, by a methoxy,methylsulphenyl, methylsulphinyl, methylsulphonyl, amino, acetylamino,benzoylamino or methanesulphonylamino group, or, if A represents anamino group and B represents a bond, an indanylene or1,2,3,4-tetrahydronaphthylene group, wherein the saturated ring is boundto the group A and the aromatic ring is bound to the cyclic ureaskeleton,

a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene,cyclohexylene or piperidinylene group, whilst the nitrogen atom may notbe bound to a nitrogen atom of the cyclic urea,

a second of the groups R_(a) to R_(d) represents a group of formula

    F-E-D-

wherein D represents a C₁₋₄ -alkylene group,

a phenylene group which may be substituted by a fluorine, chlorine orbromine atom or by a methyl, methoxy, methylsulphenyl, methylsulphinylor methylsulphonyl group,

a pyridinylene, cyclohexylene or piperidinylene group, whilstadditionally in a pyridinylene group the --CH═N-- group may be replacedby a --CO--NH-- group and the nitrogen atom, instead of being bound tothe hydrogen atom, may also be bound to the group E, provided that thelatter is not a bond or is not bound to the group D by a heteroatom, or

a --CH₂ CH₂ --N(COCH₃)--CH₂ -- group wherein the ethylene moiety isbound to the cyclic urea,

E represents a bond,

an ethylene group optionally substituted by one or two methyl groups orby an amino or dibenzylamino group,

an ethenylene or phenylene group or

a methylene group linked to group D by the group W', wherein W'represents an oxygen or sulphur atom or a sulphinyl or sulphonyl group,and

F represents a carbonyl group which is substituted by a hydroxy group orby a C₁₋₄ -alkoxy group, or F may represent a phosphono,O-methylphosphono or tetrazol-5-yl group, whilst if A represents anamino or aminoalkyl group optionally benzyloxycarbonylated at thenitrogen atom, the shortest distance between the nitrogen atom of thisgroup and the group F is at least 10 bonds,

the third of the groups R_(a) to R_(d) represents a hydrogen atom or amethyl, ethyl or phenyl group and

the fourth of the groups R_(a) to R_(d) represents a hydrogen atom or amethyl group,

the tautomers, the stereoisomers including the mixtures thereof and theaddition salts thereof.

Most particularly preferred compounds of general formula I above arethose wherein

X represents a carbonyl or sulphonyl group,

Y represents an ethylene or ethenylene group optionally substituted byR_(c) or R_(d) and optionally substituted by a methyl or phenyl group,or Y represents a carbonylmethylene or methylenecarbonyl groupoptionally substituted by a methyl group, or Y represents a --CH═N-- or--N═CH-- group optionally substituted by R_(c) or R_(d), one of thegroups R_(a) to R_(d) represents a group of formula

    A-B-C-

wherein

A represents an aminomethyl or amidino group optionally substituted byan alkoxycarbonyl group with a total of 2 to 5 carbon atoms,

B represents a bond or a 1,4-phenylene group and

C represents a 1,4-phenylene group optionally substituted by a methylgroup, 3,6-pyridazinylene or 1,4-piperidinylene group, whilst thenitrogen atom may not be bound to a nitrogen atom of the cyclic urea,or, if A represents an amino and B represents a bond, an indanylenegroup, wherein the saturated ring is attached to A and the aromatic ringto the cyclic urea ring,

a second of the groups R_(a) to R_(d) represents a group of the formula

    F-E-D-

wherein D represents a C₁₋₄ -alkylene group, a 1,4-phenylene or1,4-cyclohexylene group,

E represents a bond,

an ethylene group optionally substituted by an amino or dibenzylaminogroup,

an ethenylene group,

a 1,4-phenylene group or

a methylene group linked by the group W' to the group D, wherein W'represents an oxygen or sulphur atom or a sulphinyl or sulphonyl group,

F represents a carbonyl group which is substituted by a hydroxy group orby a C₁₋₄ -alkoxy group, whilst if A represents an aminomethyl group,the shortest distance between the nitrogen atom of this group and thegroup F is at least 10 bonds,

the third of the groups R_(a) to R_(d) represents a hydrogen atom or amethyl, ethyl or phenyl group and

the fourth of the groups R_(a) to R_(d) represents a hydrogen atom or amethyl group,

particularly those compounds of general formula I wherein there is afurther ring member between the linking points of those of groups R_(a)to R_(d) which represent the A-B-C- and F-E-D- groups, on the cyclicurea,

the tautomers, the stereoisomers including mixtures thereof and theaddition salts thereof.

The new compounds may, for example, be prepared by the followingprocesses:

a) In order to prepare compounds of general formula I wherein Frepresents a carboxy group:

Converting a compound of general formula ##STR3## wherein R_(a), R_(b),X and Y are defined as hereinbefore with the proviso that one of thegroups R_(a) to R_(d) must represent a group of formula

    F'-E-D-

wherein E and D are as hereinbefore defined and F' represents a groupwhich may be converted into a carboxyl group by hydrolysis, treatmentwith acids, thermolysis or hydrogenolysis, into a compound of generalformula I wherein F represents a carboxyl group.

For example: functional derivatives of the carboxyl group such as theunsubstituted or substituted amides, esters, thioesters,trimethylsilylesters, orthoesters, iminoesters, amidines or anhydrides,or the nitrile group may be converted by hydrolysis into a carboxylgroup; esters with tertiary alcohols, e.g. the tert.-butylester, may beconverted by treatment with an acid or thermolysis into a carboxylgroup; and esters with aralkanols, e.g. the benzylester, may beconverted by hydrogenolysis into a carboxyl group.

The hydrolysis is expediently carried out either in the presence of anacid such as hydrochloric, sulphuric, phosphoric, trichloroacetic ortrifluoroacetic acid, in the presence of a base such as lithiumhydroxide, sodium hydroxide or potassium hydroxide in a suitable solventsuch as water, water/methanol, water/ethanol, water/isopropanol,methanol, ethanol or water/dioxane at temperatures between -10° C. and120° C., e.g. at temperatures between ambient temperature and theboiling temperature of the reaction mixture. In the case of treatmentwith an organic acid such as trichloroacetic or trifluoroacetic acid,any alcoholic hydroxy groups present may simultaneously be convertedinto a corresponding acyloxy group such as the trifluoroacetoxy group.

If F' in a compound of formula II represents a cyano or aminocarbonylgroup, these groups may also be converted into the carboxyl group with anitrite, e.g. sodium nitrite, in the presence of an acid such assulphuric acid, which may expediently be used as solvent at the sametime, at temperatures between 0° and 50° C.

If F' in a compound of formula II represents, for example, thetert.-butyloxycarbonyl group, the tert.-butyl group may also be cleavedby treatment with an acid such as trifluoroacetic acid, formic acid,p-toluenesulphonic acid, sulphuric acid, phosphoric acid orpolyphosphoric acid, optionally in an inert solvent such as methylenechloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane,preferably at temperatures between -10° and 120° C., e.g. attemperatures between 0° and 60° C., or thermally, optionally in an inertsolvent such as methylene chloride, chloroform, benzene, toluene,tetrahydrofuran or dioxane and preferably in the presence of a catalyticquantity of an acid such as p-toluenesulphonic acid, sulphuric acid,phosphoric acid or polyphosphoric acid, preferably at the boilingtemperature of the solvent used, e.g. at temperatures between 40° C. and100° C.

If F' in a compound of formula II represents, for example, thebenzyloxycarbonyl group, the benzyl group may also be cleavedhydrogenolytically in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxane ordimethylformamide, preferably at temperatures between 0° and 50° C.,e.g. at ambient temperature, under a hydrogen pressure of from 1 to 5bar. During hydrogenolysis, other groups may be reduced at the sametime, e.g. a nitro group to the amino group or a benzyloxy group to thehydroxy group.

b) In order to prepare compounds of general formula I wherein Arepresents an H₂ N--C(═NH)-- group optionally substituted by an alkylgroup:

Reaction of a compound of general formula ##STR4## optionally formed inthe reaction mixture, wherein

R_(a), R_(b), X and Y are as hereinbefore defined, with the proviso thatone of the groups R_(a) to R_(d) represents a group of the formula

    Z.sub.1 -C(═NH)-B-

wherein B and C are as hereinbefore defined and Z₁ represents an alkoxyor aralkoxy group such as a methoxy, ethoxy, n-propoxy, isopropoxy orbenzyloxy group or an alkylthio or aralkylthio group such as amethylthio, ethylthio, n-propylthio or benzylthio group or an aminogroup,

with an amine of general formula

    R.sub.4 -NH.sub.2                                          (IV)

wherein

R₄ represents a hydrogen atom or a C₁₋₄ -alkyl group, or with the acidaddition salts thereof.

The reaction is expediently carried out in a solvent such as methanol,ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxaneat temperatures between 0° and 150° C., preferably at temperaturesbetween 20° and 120° C., with a corresponding free amine or with acorresponding acid addition salt such as the corresponding ammoniumcarbonates, acetates or chlorides.

A compound of general formula III is obtained for example by reacting acorresponding nitrile with a corresponding alcohol such as methanol,ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of anacid such as hydrochloric acid or by reacting a corresponding amide witha trialkyloxonium salt such as triethyloxonium-tetrafluoroborate in asolvent such as methylene chloride, tetrahydrofuran or dioxane attemperatures between 0° and 50° C., but preferably at 20° C., or acorresponding nitrile with hydrogen sulphide, appropriately in a solventsuch as pyridine or dimethylformamide and in the presence of a base suchas triethylamine and subsequent alkylation of the thioamide formed witha corresponding alkyl or aralkyl halide, or by reacting a correspondingnitrile with an alkoxide such as sodium methoxide in a solvent such asdioxane or tetrahydrofuran, but preferably in the alcohol in question.

c) In order to prepare compounds of general formula I wherein at leastone of groups B, C, D or E contains a sulphinyl or sulphonyl group:

Oxidation of a compound of general formula ##STR5## wherein R_(a),R_(b), X and Y are as hereinbefore defined, with the proviso that atleast one of the groups Y, B, C, D or E contains a sulphenyl orsulphinyl group.

The oxidation is preferably carried out in a solvent or mixture ofsolvents, e.g. in water, water/pyridine, acetone, methylene chloride,glacial acetic acid, glacial acetic acid/acetic hydride, dilutesulphuric acid or trifluoroacetic acid, and depending on the oxidisingagent used at temperatures between -80° and 100° C.

In order to prepare a corresponding S-oxide compound of general formulaI the oxidation is conveniently carried out with one equivalent of theoxidizing agent used, eg. with hydrogen peroxide in glacial acetic acid,trifluoroacetic acid or formic acid at 0° to 20° C. or in acetone at 0°to 60° C., with a peracid such as performic acid in glacial acetic acidor trifluoroacetic acid at 0° to 50° C. or with m-chloro-perbenzoic acidin methylene chloride or chloroform at -20° to 60° C., with sodiummetaperiodate in aqueous methanol or ethanol at -15° to 25° C., withbromine in glacial acetic acid or aqueous acetic acid optionally in thepresence of a weak base such as sodium acetate, with N-bromo-succinimidein ethanol, with tert.butyl hypochlorite in methanol at -80° to -30° C.,with iodobenzodichloride in aqueous pyridine at 0° to 50° C., withnitric acid in glacial acetic acid at 0 to 20° C., with chromic acid inglacial acetic acid or in acetone at 0° to 20° C. and with sulphurylchloride in methylene chloride at -70° C., with the thioether-chlorinecomplex so obtained conveniently being hydrolysed with aqueous ethanol.

In order to prepare an S,S-dioxide compound of general formula I theoxidation is conveniently carried out, starting from a correspondingalkylsulphinyl compound, with one or more equivalents of the oxidisingagent used, or starting from a corresponding alkylsulphenyl compoundwith two or more equivalents of the oxidising agent used, e.g. withhydrogen peroxide in glacial acetic acid/acetic anhydride,trifluoroacetic acid or in formic acid at 20° to 100° C. or in acetoneat 0° to 60° C., with a peracid such as performic acid orm-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid,methylene chloride or chloroform at temperatures between 0° and 60° C.,with nitric acid in glacial acetic acid at 0° to 20° C., with chromicacid or potassium permanganate in glacial acetic acid, water/sulphuricacid or in acetone at 0° to 20° C.

d) In order to prepare compounds of general formula I wherein Yrepresents a straight-chained C₂₋₄ -alkylene group, optionallysubstituted by R_(c) or R_(d) or by R_(c) and R_(d), which may be mono-or disubstituted by alkyl, trifluoromethyl, aralkyl, aryl or heteroarylgroups:

Hydrogenation of a compound of general formula ##STR6## wherein R_(a),R_(b) and X are as hereinbefore defined and Y' represents astraight-chained C₂₋₄ -alkenylene group, optionally substituted by R_(c)or R_(d) or by R_(c) and R_(d), which may be mono- or disubstituted byalkyl, trifluoromethyl, aralkyl, aryl or heteroaryl groups.

The hydrogenation is carried out in a solvent such as methanol, ethanol,ethyl acetate or glacial acetic acid, optionally with the addition of anacid such as hydrochloric acid, with hydrogen in the presence of acatalyst such as palladium/charcoal or platinum, at temperatures between0° and 100° C., but preferably between 20° and 50° C., and under ahydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.

e) In order to prepare compounds of general formula I wherein Arepresents an aminoalkyl, amidino or guanidino group substituted by analkoxycarbonyl group having a total of 2 to 5 carbon atoms or by anaralkoxycarbonyl, aryloxycarbonyl, alkylcarbonyl or arylcarbonyl group:

Reaction of a compound of general formula ##STR7## wherein R_(a), R_(b),X and Y are as hereinbefore defined with the proviso that one of thegroups R_(a) to R_(d) represents a group of formula

    A'-B-C-

wherein

B and C are as hereinbefore defined and A' represents an H₂ N--C₁₋₅alkyl--, H₂ N--C(═NH)-- or H₂ N--C(═NH)--NH-- group, with a compound ofgeneral formula

    Z.sub.2 -R.sub.5                                           (VIII)

wherein

R₅ represents an alkoxycarbonyl group having a total of 2 to 5 carbonatoms, an aralkoxycarbonyl, aryloxycarbonyl, alkylcarbonyl orarylcarbonyl group and Z₂ represents a nucleophilic leaving group suchas a halogen atom, e.g. a chlorine or bromine atom, or an aryloxy,arylthio, alkoxycarbonyloxy, aralkoxy-carbonyloxy or imidazolyl group.

The acylation is conveniently carried out in a solvent such astetrahydrofuran, methylene chloride, chloroform, dimethylformamide,water or mixtures of these solvents, optionally in the presence of abase such as sodium carbonate, potassium carbonate or sodium hydroxidesolution or in the presence of a tertiary organic base such astriethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine orpyridine, which may simultaneously serve as solvents, at temperaturesbetween -30° and 100° C., but preferably at temperatures between -10°and 80° C.

f) In order to prepare compounds of general formula I wherein Frepresents a carbonyl group substituted by a C₁₋₆ -alkoxy group, whereinan alkoxy group with 1 to 3 carbon atoms may be substituted in the 1-,2- or 3-position by an aryl or heteroaryl group or in the 2- or3-position by a pyrrolidin-2-on-1-yl, morpholino, thiomorpholino or1-oxido-thiomorpholino group:

Reacting a compound of general formula ##STR8## wherein R_(a), R_(b), Xand Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) represents a group of formula

    F"-E-D-

wherein

E and D are as hereinbefore defined and F" represents a carboxy oralkoxycarbonyl group, with an alcohol of general formula

    HO-R.sub.6                                                 (X)

wherein

R₆ represents a C₁₋₆ -alkyl group which may be substituted in the 1-, 2-or 3-position by an aryl or heteroaryl group or in the 2- or 3-positionby a pyrrolidin-2-on-1-yl, morpholino, thiomorpholino or1-oxido-thiomorpholino group.

The-reaction is expediently carried out in a solvent or mixture ofsolvents such as methylene chloride, dimethylformamide,dimethylsulphoxide, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane, optionally in the presence of anacid such as hydrochloric acid or in the presence of a dehydratingagent, e.g. in the presence of isobutylchloroformate, thionylchloride,trimethylchloro-silane, hydrochloric acid, sulphuric acid,methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride,phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or1-hydroxy-benzotriazole and optionally also in the presence of4-dimethylamino-pyridine, N,N'-carbonyldiimidazole orN,N'-thionyl-diimidazole or triphenylphosphine/carbon tetrachloride,conveniently at temperatures between 0° and 150° C., preferably attemperatures between 0° and 50° C.

The reaction of a corresponding alkoxy compound with an alcohol ofgeneral formula X is preferably carried out in a corresponding alcoholas solvent, optionally in the presence of an additional solvent such asmethylene chloride or ether, preferably in the presence of an acid suchas hydrochloric acid at temperatures between 0° and 100° C., preferablyat temperatures between 20 and 80° C.

g) In order to prepare compounds of general formula I wherein Arepresents an NH₂ --C(═NH)-- group and B or, if B represents a bond, Crepresents a C₄₋₅ -cycloalkylene group, optionally substituted by analkyl, aralkyl or aryl group, wherein a CH moiety is replaced by anitrogen atom, or a C₆₋₇ -cycloalkylene group, optionally substituted byan alkyl, aralkyl or aryl group, wherein one or two CH moieties in the1,4-position relative to each other are each replaced by a nitrogenatom, whilst B or, if B is a bond, C is linked to the group A via one ofthe above-mentioned nitrogen atoms:

Reacting a compound of general formula ##STR9## wherein R_(a), R_(b), Xand Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) represents a group of formula

    H-B'-C- or H-C'-

wherein

C is as hereinbefore defined and B' or C' represents a C₄₋₅-cycloalkylene group, optionally substituted by an alkyl, aralkyl oraryl group, wherein a CH moiety is replaced by a nitrogen atom, or aC₆₋₇ -cycloalkylene group, optionally substituted by an alkyl, aralkylor aryl group, wherein one or two CH moieties in the 1,4-positionrelative to each other are each replaced by a nitrogen atom, thehydrogen atom being linked to a nitrogen atom of the group B' or C',with a compound of general formula

    Z.sub.3 --C(═NH)--NH.sub.2                             (XII)

wherein

Z₃ represents a nucleophilic leaving group such as an alkoxy oralkylthio group, e.g. a methylthio or ethylthio group.

The reaction is conveniently carried out in a solvent or mixture ofsolvents such as dimethylformamide, dimethylsulphoxide, benzene,toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran ordioxane, preferably in the presence of an acid-binding agent, e.g. analkoxide such as potassium tert.-butoxide, an alkali metal hydroxidesuch as sodium or potassium hydroxide, an alkali metal carbonate such assodium carbonate or potassium carbonate or an alkali metal hydride suchas sodium hydride, conveniently at temperatures between 50° and 150° C.,preferably at temperatures between 75° and 125° C.

h) In order to prepare compounds of general formula I, wherein Arepresents an H₂ N--CH₂ --V-- group, wherein V represents a bond or astraight-chained or branched C₁₋₄ -alkylene group:

Reduction of a compound of general formula ##STR10## wherein R_(a),R_(b), X and Y are as hereinbefore defined with the proviso that one ofthe groups R_(a) to R_(d) represents a group of the formula

    NC-V-B-C-

wherein

B and C are as hereinbefore defined and V represents a bond or astraight-chained or branched C₁₋₄ -alkylene group.

The reduction is preferably carried out in a suitable solvent such asmethanol, methanol/water, methanol/water/ammonia, ethanol, ether,tetrahydrofuran, dioxane or dimethylformamide, optionally with theaddition of an acid such as hydrochloric acid, in the presence ofcatalytically activated hydrogen, e.g. hydrogen in the presence of Rneynickel, platinum or palladium/charcoal, or in the presence of a metalhydride such as sodium borohydride, lithium borohydride or lithiumaluminium hydride, at temperatures between 0° and 100° C., preferably attemperatures between 20° and 80° C.

i) In order to prepare compounds of general formula I wherein Crepresents an alkylene group substituted by a hydroxy group:

Reduction of a compound of general formula ##STR11## wherein R_(a),R_(b), X and Y are as hereinbefore defined, with the proviso that one ofthe groups R_(a) to R_(d) represents a group of the formula

    A-B-C"-

wherein

A and B are as hereinbefore defined and C" represents an alkylene groupwherein a methylene group is replaced by a carbonyl group.

The reduction is preferably carried out in a suitable solvent such asmethanol, methanol/water, ethanol, ether, tetrahydrofuran, dioxane orglacial acetic acid, in the presence of catalytically activatedhydrogen, e.g. hydrogen in the presence of platinum orpalladium/charcoal, or in the presence of a metal hydride such as sodiumborohydride, lithium borohydride or lithium aluminium hydride, attemperatures between -5° and 20° C., preferably at temperatures between0° and 10° C.

j) In order to prepare compounds of general formula I wherein Arepresents an H₂ N--C(═NH)--NH-- group:

Reacting a compound of general formula ##STR12## wherein R_(a), R_(b), Xand Y are as hereinbefore defined with the proviso that one of the groupR_(a) to R_(d) represents a group of the formula

    H.sub.2 N-B-C-

wherein

B and C are as hereinbefore defined, with cyanamide or an acid additionsalt thereof or with an S-alkyl-isothiourea, O-methylisothiourea or1-amidino-3,5-dimethylpyrazole.

The reaction is conveniently carried out in a solvent such as dioxane,dioxane/water or tetrahydrofuran, preferably at temperatures between 60°and 120° C., e.g. at the boiling temperature of the reaction mixture.

k) Cyclising a compound of general formula ##STR13## wherein R_(a),R_(b) and X are as hereinbefore defined, one of the groups U₁ or U₂represents a hydrogen atom and the other group U₁ or U₂ represents agroup of the formula

    -Y"-Z.sub.4

wherein

Y" represents a straight-chained alkylene or alkenylene group eachhaving 2 to 4 carbon atoms, optionally substituted by R_(c) or R_(d) orby R_(c) and R_(d), wherein each carbon atom may be mono- ordisubstituted by an alkyl, trifluoromethyl, aralkyl, aryl, heteroaryl oralkylcarbonyl group, whilst the substituents may be identical ordifferent, or Y" represents a 1,2-cycloalkylene group having 4 to 7carbon atoms optionally substituted by R_(c) or R_(d) or by R_(c) andR_(d), or Y" represents a 1,2-cycloalkenylene group having 4 to 7 carbonatoms, a --CH═N-- group optionally substituted by the groups R_(c) orR_(d), wherein the nitrogen atom is linked to one of the nitrogen atomsin formula XVI, or a --CH₂ --NH-- group optionally substituted by R_(c)or R_(d) and Z₄ represents a nucleophilic leaving group such as ahalogen atom, a hydroxy, alkoxy or sulphonic acid ester group, e.g. achlorine, bromine or iodine atom, a methoxy, ethoxy, isopropyloxy,methanesulphonyloxy or p-toluenesulphonyloxy group, or, together with anadjacent methylene group of the group Y", Z₄ represents a carbonyl,carboxy, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl ordialkoxymethyl group.

The reaction is preferably carried out in a solvent such as ethanol,isopropanol, methylene chloride, dioxane, toluene, dimethylformamide ordimethyl-sulphoxide, optionally in the presence of a base such aspyridine, an acid such as hydrochloric, sulphuric, polyphosphoric ortrifluoroacetic acid, and a dehydrating agent such asN,N'-dicyclohexylcarbodiimide, at temperatures between 20° and 200° C.However, the reaction may also be carried out without a solvent.

If Z₄ represents a nucleophilic leaving group such as a halogen atom ora sulphonic ester group, the reaction is preferably carried out in thepresence of a base such as potassium carbonate, sodium hydride orpotassium tert.butoxide, at temperatures between 20° and 60° C., if thegroup Z₄ represents a hydroxy or alkoxy group or together with anadjacent methylene group of the group Y" represents a carbonyl, carboxy,alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl or dialkoxymethylgroup, the reaction is preferably carried out in the presence of an acidsuch as hydrochloric or trifluoroacetic acid, which may simultaneouslyserve as solvent, at temperatures between 20° and 80° C., or in the meltat temperatures between 50° and 250° C., preferably at temperaturesbetween 100° and 200° C.

l) In order to prepare compounds of general formula I wherein R_(a) orR_(c) represents an E-F-D- group:

Cyclising a compound of general formula

    R.sub.c --CO--CHR.sub.d --NR.sub.a --CO--NHR.sub.b         (XVII)

optionally formed in the reaction mixture, wherein R_(a) to R_(d) are ashereinbefore defined, optionally with subsequent hydrogenation.

The cyclisation is preferably carried out in a solvent such as water,ethanol/water, ethanol, benzene, toluene or dioxane and conveniently inthe presence of a base such as pyridine, which may also serve assolvent, at elevated temperatures, e.g. at the boiling temperature ofthe solvent used.

The optional subsequent hydrogenation is preferably carried out usinghydrogen in the presence of a catalyst such as palladium/charcoal orplatinum, in a solvent such as methanol, ethanol, ethyl acetate orglacial acetic acid, optionally with the addition of an acid such ashydrochloric acid, at temperatures between 0° and 50° C., but preferablyat ambient temperature, and under a hydrogen pressure of 1 to 7 bar,preferably 3 to 5 bar.

m) In order to prepare compounds of general formula I wherein Xrepresents a carbonyl group:

Reacting a compound of general formula

    R.sub.a --NH--Y--NH--R.sub.b                               (XVIII)

wherein

R_(a), R_(b) and Y are as hereinbefore defined, with a compound ofgeneral formula

    Z.sub.5 --CO--Z.sub.6                                      (XIX)

wherein

Z₅ and Z₆, which may be identical or different, represent nucleophilicleaving groups such as halogen atoms, alkoxy or aryloxy groups, e.g.they each represent a chlorine atom or a methoxy, ethoxy or phenyloxygroup.

The reaction is preferably carried out in a solvent such as methylenechloride, chloroform, toluene or dioxane, optionally in the presence ofa base such as triethylamine or pyridine at temperatures between 0° and50° C., preferably at ambient temperature.

n) In order to prepare compounds of general formula I wherein R_(a) toR_(d) are defined as hereinbefore, with the proviso that at least one ofthe groups R_(a) and R_(b) does not represent a hydrogen atom:

Reacting a compound of general formula ##STR14## wherein X and Y are ashereinbefore defined, one of the groups R_(a) or R_(b) represents ahydrogen atom and the other group R_(a) or R_(b) is as hereinbeforedefined, with a compound of general formula

    Z.sub.7 --R'                                               (XXI)

wherein

R' has the meanings given hereinbefore for R_(a) or R_(b), with theexception of a hydrogen atom, and Z₇ represents a nucleophilic leavinggroup such as a halogen atom or a sulphonic acid ester group, e.g. achlorine, bromine or iodine atom or a methane-sulphonyloxy orp-toluenesulphonyloxy group

or, if R_(a) or R_(b) represents a --D--COO-alkyl group, with theproviso that there are two carbon atoms between the nitrogen atom of thecyclic urea and the alkoxycarbonyl group, reacting with a compound ofgeneral formula

    -D'-COO-alkyl                                              (XXII)

wherein

D' has the meanings given for D hereinbefore, with the proviso that thealkoxycarbonyl group immediately precedes a carbon-carbon double ortriple bond.

The alkylation is expediently carried out in a solvent or mixture ofsolvents such as methylene chloride, dimethylformamide,dimethylsulphoxide, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane, preferably in the presence of anacid binding agent, e.g. an alkoxide such as potassium tert.butoxide, analkali metal hydroxide such as sodium or potassium hydroxide, an alkalimetal carbonate such as potassium carbonate, an alkali metal amide suchas sodium amide or an alkali metal hydride such as sodium hydride or atertiary organic base such as ethyl-diisopropylamine, conveniently attemperatures between 0° and 150° C., preferably at temperatures between0° and 50° C.

The arylation is expediently carried out with an aryl compound ofgeneral formula XXI wherein Z₇ represents an iodine atom, preferably ina solvent such as toluene or xylene, and preferably in the presence ofone or more reaction accelerators such astris-[2-(2-methoxy-ethoxy)ethyl]amine, copper(I)chloride orcopper(II)chloride, at elevated temperatures, e.g. at temperaturesbetween 100° and 200° C., but preferably at the boiling temperature ofthe reaction mixture. However, the reaction may also be carried outwithout a solvent.

The addition of an alkenyl compound of general formula XXII ispreferably carried out in a solvent such as dimethylformamide and in thepresence of a base such as sodium hydride, at temperatures between 0°and 50° C., preferably at ambient temperature.

o) In order to prepare compounds of general formula I wherein Frepresents a carboxy, alkoxycarbonyl, aralkoxycarbonyl oraryloxycarbonyl group:

Oxidation of a compound of general formula ##STR15## wherein R_(a),R_(b), X and Y are as hereinbefore defined, with the proviso that one ofthe groups R_(a) to R_(d) represents a group of the formula

    CH.sub.2 ═CH-E-D-

where E and D are as hereinbefore defined, with optional subsequentesterification.

The oxidation is carried out in a solvent such as methylene chloride,acetonitrile, acetonitrile/water, methylene chloride/acetonitrile/wateror carbon tetrachloride/acetonitrile/water, in the presence of anoxidising agent such as potassium permanganate or ruthenium tetroxide,the ruthenium tetroxide preferably being formed in the reaction mixtureby reacting a ruthenium salt such as ruthenium trichloride with anoxidising agent such as sodium periodate, at temperatures between -10°and 50° C., preferably at temperatures between 15° and 30° C.

The optional subsequent esterification is expediently carried out in asuitable solvent, e.g. in a corresponding alcohol, pyridine, toluene,methylene chloride, tetrahydrofuran or dioxane, in the presence of anacid activating and/or dehydrating agent such as hydrogen chloride,concentrated sulphuric acid, thionyl chloride, ethylchloroformate,carbonyldiimidazole or N,N'-dicyclohexylcarbodiimide or the isoureaesters thereof, optionally in the presence of a reaction acceleratorsuch as copper chloride, or by transesterification, e.g. with acorresponding carbonic acid diester, at temperatures between 0° and 100°C., but preferably at temperatures between 20° C. and the boilingtemperature of the solvent in question.

p) In order to prepare compounds of general formula I wherein Frepresents an O-alkyl-phosphono group:

Reacting a compound of general formula ##STR16## wherein R_(a), R_(b), Xand Y are as hereinbefore defined, with the proviso that F represents adialkoxyphosphoryl group, with an alkali metal iodide.

The reaction is preferably carried out in a solvent suchmethylethylketone, in the presence of an alkali metal iodide such assodium iodide, at temperatures between 25° and 100° C., preferably atthe boiling temperature of the reaction mixture.

q) In order to prepare compounds of general formula I wherein Frepresents a phosphono group:

Reacting a compound of general formula ##STR17## wherein R_(a), R_(b), Xand Y are as hereinbefore defined, with the proviso that F represents anO-alkylphosphono- or dialkoxyphosphoryl group, with an alkali metaliodide in the presence of a trialkylhalosilane.

The reaction is preferably carried out in a solvent such asacetonitrile, in the presence of an alkali metal iodide such as sodiumiodide, and a trialkylhalosilane such as trimethylchlorosilane, attemperatures between 25° and 80° C., but preferably at temperaturesbetween 30° and 50° C.

r) In order to prepare compounds of general formula I wherein Wrepresents an R₁ N-- group:

Reacting a compound of general formula ##STR18## wherein R_(a), R_(b), Xand Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) represents a Z₈ --D"-- group, wherein D"represents a C₁₋₃ -alkylene group and Z₈ represents a nucleophilicleaving group such as a halogen atom or a sulphonic acid ester group,e.g. a chlorine, bromine or iodine atom or a methane-sulphonyloxy orp-toluenesulphonyloxy group, with a compound of general formula

    R.sub.1 NH-E'-F                                            (XXVII)

wherein

F and R₁ are as hereinbefore defined and E' represents a C₁₋₃ -alkylenegroup.

The reaction is expediently carried out in a solvent or mixture ofsolvents such as methylene chloride, dimethylformamide,dimethylsulphoxide, benzene, toluene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane, preferably in the presence of anacid binding agent, e.g. an alkoxide such as potassium tert.butoxide, analkali metal hydroxide such as sodium or potassium hydroxide, an alkalimetal carbonate such as potassium carbonate, an alkali metal amide suchas sodium amide or an alkali metal hydride such as sodium hydride or atertiary organic base such as ethyl diisopropylamine, conveniently attemperatures between 0° and 150° C., preferably at temperatures between0° and 50° C.

s) In order to prepare compounds of general formula I wherein Arepresents an amino or aminoalkyl group:

Reacting a compound of general formula ##STR19## wherein R_(a), R_(b), Xand Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) represents an H₂ N--CO--T--B--C-- group, where Band C are as hereinbefore defined and T represents a bond or a C₁₋₅-alkylene group, with a phenyl iodine(III) compound of general formula##STR20## wherein R₇ represents an acyl group or an organic carboxylicacid such as the acetoxy or trifluoroacetoxy group.

The-reaction is preferably carried out in an aqueous solvent such aswater or water/acetonitrile. at temperatures between 0° and 50° C., butpreferably at ambient temperature.

t) In order to prepare compounds of general formula I wherein Arepresents an amino or aminoalkyl group substituted by one or two alkylgroups at the nitrogen atom:

Reacting a compound of general formula ##STR21## wherein R_(a), R_(b), Xand Y are as hereinbefore defined, with the proviso that one of thegroups R_(a) to R_(d) represents a group of the formula

    A"-B-C-

wherein

B and C are as hereinbefore defined and A" represents an amino,alkylamino, aminoalkyl or alkylaminoalkyl group, with a compound ofgeneral formula

    Z.sub.9 --(R.sub.8 --C--R.sub.9)--Z.sub.10                 (XXXI)

wherein

R₈ and R₉, which may be identical or different, represent hydrogen atomsor alkyl groups, one of the groups Z₉ or Z10 represents a nucleophilicleaving group such as a halogen atom, e.g. a chlorine, bromine or iodineatom, or a sulphonic acid ester group, e.g. a methanesulphonyloxy orp-toluenesulphonyloxy group, and the other group Z₉ or Z₁₀ represents ahydrogen atom or analkyl group or Z₉ and Z₁₀ together represent anoxygen atom.

The alkylation with a compound of formula XXXI wherein Z₉ or Z₁₀represents a nucleophilic leaving group is conveniently carried out in asolvent such as tetrahydrofuran, dioxane, dimethylsulphoxide ordimethylformamide, optionally in the presence of a base such as sodiumcarbonate, potassium carbonate or sodium hydroxide solution or in thepresence of a tertiary organic base such as N-ethyl-diisopropylamine orN-methyl-morpholine, which may be simultaneously serve as solvent, attemperatures between -30° and 100° C., but preferably at temperaturesbetween -10° and 80° C.

The alkylation with a carbonyl compound of general formula XXXI ispreferably carried out in the presence of a complex metal hydride suchas sodium borohydride, lithium borohydride or sodium cyanoborohydride,conveniently at a pH of 6 to 7 and at ambient temperature or in thepresence of a hydrogenation catalyst, e.g. with hydrogen in the presenceof palladium/charcoal, at a hydrogen pressure of 5 bar.

u) In order to prepare compounds of general formula I wherein Arepresents a cyano group:

Reacting a compound of general formula ##STR22## wherein R_(a), R_(b), Xand Y are defined as hereinbefore, with the proviso that one of thegroups R_(a) to R_(d) represents a group of the formula

    A"'-B-C-

wherein

B and C are as hereinbefore defined and A"' represents a halogen atom,e.g. a bromine or iodine atom, with copper(I)cyanide.

The reaction is preferably carried out in a solvent such asdimethylformamide, dimethylacetamide or N-methyl-pyrrolidone, attemperatures between 100° and 250° C., preferably between 150° C. andthe boiling temperature of the reaction mixture.

v) In order to prepare compounds of general formula I wherein Arepresents an aminoalkyl group where the amino group is not bound to aquaternary carbon atom, or an amino group which is bound to a CH-- orCH₂ group of group B or C:

Reduction of a compound of general formula ##STR23## wherein R_(a),R_(b), X and Y are as hereinbefore defined, with the proviso that one ofthe groups R_(a) to R_(d) represents a group of the formula

    A""-B-C-

wherein

B and C are as hereinbefore defined and A"" contains an N-hydroxy-iminogroup.

The reduction is preferably carried out in a suitable solvent such asmethanol, methanol/water, methanol/water/ammonia, ethanol, ether,tetrahydrofuran, dioxane or dimethylformamide, optionally with theaddition of an acid such as hydrochloric acid, in the presence ofcatalytically activated hydrogen, e.g. hydrogen in the presence of Rneynickel, platinum or palladium/charcoal, at temperatures between 0° and100° C., preferably at temperatures between 20° and 80° C.

If according to the invention a compound of general formula I isobtained, this may be converted by bromination into a correspondingbromine compound of general formula I or

if a compound of general formula I is obtained, this may be converted bynitrogenation into a corresponding nitro compound of general formula Ior

if a compound of general formula I is obtained which contains a nitrogroup, this may be converted by reduction into a corresponding aminocompound or

if a compound of general formula I is obtained which contains an R₁ NH--group or wherein W represents an imino group, this may be converted byacylation or sulphonation into a corresponding compound of generalformula I which contains an R₁ NH-- group substituted by analkylcarbonyl, aralkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkylsulphonyl, aralkylsulphonyl or arylsulphonyl group, or

if a compound of general formula I is obtained wherein X represents acarbonyl group, this may be converted by means of a sulphurising agentinto a corresponding thiocarbonyl compound.

The subsequent bromination is preferably carried out in a solvent suchas glacial acetic acid, with a brominating agent such as bromine, attemperatures between 0° and 40° C., preferably at ambient temperature.

The subsequently nitrogenation is carried out with a nitrogenating agentsuch as concentrated sulphuric acid/nitric acid or fuming nitric acid,which may conveniently serve as solvents, optionally in a solvent suchas nitrobenzene, at temperatures between 0° and 50° C., preferably atambient temperature.

The subsequent reduction of the nitro group is preferably carried out ina solvent such as water, water/ethanol, methanol, glacial acetic acid,ethyl acetate or dimethylformamide, expediently with hydrogen in thepresence of a hydrogenation catalyst such as Rney nickel, platinum orpalladium/charcoal, with metals such as iron, tin or zinc in thepresence of an acid such as zinc/acetic acid or zinc/calcium chloride,with salts such as iron(II)sulphate, tin(II)chloride, sodium sulphide,sodium hydrogen sulphite or sodium dithionite, or with hydrazine in thepresence of Rney nickel, at temperatures between 0° and 100° C., butpreferably at temperatures between 20° and 80° C.

The subsequent acylation or sulphonylation of an R₁ --NH-- group isexpediently carried out in a solvent such as methylene chloride,chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane,benzene, toluene, acetonitrile or dimethylformamide, optionally in thepresence of an acid activating agent or a dehydrating agent, e.g. in thepresence of ethyl chloroformate, thionylchloride, phosphorustrichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, optionally in the presence ofan inorganic base such as sodium carbonate or a tertiary organic basesuch as triethylamine, pyridine or 4-dimethylaminopyridine, which maysimultaneously be used as solvent, at temperatures between -25° and 150°C., but preferably at temperatures between -10° C. and the boilingtemperature of the solvent used. However, the subsequent acylation orsulphonylation is preferably carried out with a corresponding acidhalide or acid anhydride, as described hereinbefore, and this may alsobe carried out without a solvent.

The reaction is carried out with a sulphurising agent such as phosphoruspentasulphide or2,4-bis-(4-methoxyphenyl)-1,3-di-thia-2,4-diphosphetan-2,4-disulphide,expediently in a solvent such as pyridine, toluene or xylene, attemperatures between 50° and 150° C., e.g. at the boiling temperature ofthe reaction mixture.

In reactions a) to v) described above and in the subsequent reactions,any reactive groups present such as hydroxy, carboxy, amino, alkylaminoor imino groups, may optionally be protected during the reaction bymeans of conventional protecting groups which are cleaved again afterthe reaction.

For example, a suitable protective group for a hydroxy group might be atrimethylsilyl, acetyl, benzoyl, tert.-butyl, trityl, benzyl ortetrahydropyranyl group, whilst protective groups for a carboxyl groupmight be the trimethylsilyl, methyl, ethyl, tert.-butyl, benzyl ortetrahydropyranyl group, and

protecting groups for an amino, alkylamino or imino group might be theacetyl, benzoyl, ethoxycarbonyl, tert.-butoxycarbonyl,benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl groupand an additional protecting group for the amino group might be thephthalyl group.

The optional subsequent cleaving of a protecting group is carried out,for example, hydrolytically in an aqueous solvent, e.g. in water,isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such as sodiumhydroxide or potassium hydroxide, or by ether cleavage, e.g. in thepresence of iodotrimethylsilane, at temperatures between 0° and 100° C.,preferably at temperatures between 10° and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved,for example, by hydrogenelysis, e.g. with hydrogen in the presence of acatalyst such as palladium/charcoal, in a solvent such as methanol,ethanol, ethyl acetate or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid, at temperatures between0° and 50° C., but preferably at ambient temperature, under a hydrogenpressure of from 1 to 7 bar, but preferably from 3 to 5 bar.

The cleaving of a methoxybenzyl group may also be carried out in thepresence of an oxidising agent such as Ce(IV)ammonium nitrate, in asolvent such as methylene chloride, acetonitrile or acetonitrile/water,at temperatures between 0° and 50° C., but preferably at ambienttemperature.

However, a 2,4-dimethoxybenzyl group is preferably cleaved intrifluoroacetic acid in the presence of anisole.

A tert.-butyl or tert.-butyloxycarbonyl group is preferably cleaved bytreatment with an acid such as trifluoroacetic or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxane or ether.

The cleaving of a phthalyl group is preferably carried out in thepresence of hydrazine or a primary amine such as methylamine, ethylamineor n-butylamine in a solvent such as methanol, ethanol, isopropanol,toluene/water or dioxane, at temperatures between 20° and 50° C.

Moreover, the compounds of general formula I obtained may, as alreadymentioned hereinbefore, be resolved into the enantiomers and/ordiastereomers thereof. Thus, for example, cis/trans mixtures may beresolved into their cis and trans isomers and compounds having at leastone optically active carbon atom may be resolved into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be separated bychromatography into their cis and trans isomers, the compounds ofgeneral formula I obtained in the form of racemates may be separated byknown methods (see Allinger N. L. and Eliel E. L. in "Topics inStereochemistry", Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I having at least 2asymmetric carbon atoms can be separated on the basis of theirphysical-chemical differences into their diastereomers by methods knownper se, e.g. by chromatography and/or fractional crystallisation, and ifthese diastereomers are obtained in racemic form they may subsequentlybe separated into the enantiomers as mentioned above.

Enantiomer separation is preferably achieved by column separation onchiral phases or by recrystallisation from an optically active solventor by reacting with an optically active substance which forms salts orderivatives such as esters or amides with the racemic compound, moreparticularly acids and their activated derivatives or alcohols, andseparating the diastereomeric salt mixture obtained in this way, e.g. onthe basis of different solubilities, whilst the free antipodes may beliberated from the pure diastereomeric salts by the action of suitableagents. Particularly common optically active acids are, for example, theD and L forms of tartaric or dibenzoyltartaric acid, di-o-tolyl-tartaricacid, malic, mandelic and camphorsulphonic acid, glutamic acid, asparticacid or quinic acid. An optically active alcohol might be, for example,(+)- or (-)-menthol and an optically active acyl group in amides mightbe (+) or (-)-menthyloxycarbonyl.

Moreover, the compounds of formula I obtained may be converted into theacid addition salts thereof, more particularly for pharmaceutical usethe physiologically acceptable salts thereof with inorganic or organicacids. Examples of suitable acids include hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid and maleic acid.

In addition, the new compounds of formula I thus obtained, should theycontain a carboxyl group, may if desired subsequently be converted intothe addition salts thereof with inorganic or organic bases, moreparticularly for pharmaceutical use into the physiologically acceptableaddition salts thereof. Examples of suitable bases include sodiumhydroxide, potassium hydroxide, cyclohexylamine, ethanolamine,diethanolamine and triethanolamine.

The compounds used as starting materials are known from the literaturein some cases or may be obtained by methods known from the literature(see the Examples), e.g. by the methods described in published Germanpatent applications DE-A-4035961 and DE-A-4102024.

For example, the cyclic urea derivatives are obtained by cyclising acorrespondingly substituted urea which in turn is obtained by knownmethods, or by reacting a correspondingly substituted diamine withphosgene and optionally subsequently introducing sulphur and oxidisingthe resulting thio compound.

As already mentioned hereinbefore, the new cyclic urea derivatives ofgeneral formula I and the addition salts thereof, particularly thephysiologically acceptable addition salts thereof with inorganic ororganic acids or bases, have valuable properties. Thus, the compounds ofgeneral formula I wherein A contains an optionally substituted amino,amidino or guanidino group or a group which can optionally be convertedin vivo into an optionally substituted amino, amidino or guanidinogroup, e.g. an amino, amidino or guanidino group substituted by analkoxycarbonyl group, and -D-E-F contains carboxyl, sulpho, phosphono,O-alkyl-phosphono or 5-tetrazolyl groups or groups which can beconverted in vivo into a carboxyl, sulpho, phosphono, O-alkyl-phosphonoor tetrazolyl group, e.g. alkoxy-substituted carbonyl groups, havevaluable pharmacological properties, not only an antiinflammatory effectwhich inhibits the breakdown of bone but in particular antithromboticand antiaggregatory effects and inhibitory effects on tumours ormetastases.

The compounds of general formula I wherein A represents a cyano orcyanoalkyl group are valuable intermediate products for preparing thecorresponding aminomethyl and amidino compounds of general formula I.

By way of example, the compounds of general formula I were tested fortheir biological effects in the following way:

1. Fibrinogen binding to human thrombocytes

Blood obtained by puncture of an antecubital vein was anticoagulatedwith trisodium citrate (final concentration: 13 mM) and centrifuged for10 minutes at 170 *g. The supernatant platelet-rich plasma was placed ona Sepharose 2B column (Pharmacia) and eluted with a solution of 90 mMcommon salt, 14 mM trisodium citrate, 5 mM glucose and 50 mMtris(hydroxymethyl)aminomethane, adjusted to pH 7.4. The gel-filteredplatelets (GFP) appearing in front of the plasma proteins were used forthe binding tests.

50 μl of a 60 mM calcium chloride solution, 50 μl of a 0.6 mM adenosinediphosphate solution, 100 μl of substance solution or solvent and 50 μlof fibrinogen solution (containing 3 μg I125-fibrinogen) were added to750 μl of GFP and incubated for 20 minutes at ambient temperature. Thenon-specific binding was measured in the presence of 3 mg/ml of coldfibrinogen.

900 μl of the incubate were carefully pipetted onto 250 μl of siliconoil (AP 38: AR 20, 1:2 v/v, Wacker Chemie) in Eppendorf vessels andcentrifuged for 2 minutes at 10,000 *g. The aqueous supernatant and someof the oil were removed, the tip of the vessel with the platelet pelletwas cut off and the quantity of bound fibrinogen was measured in agamma-counter. The concentration of substance which inhibited fibrinogenbinding by 50% was calculated from a series of concentrations and givenas the IC₅₀.

2. Antithrombotic effect

Method: The thrombocyte aggregation was measured in platelet-rich plasmafrom healthy test subjects using the Born and Cross method (J. Physiol.170: 397 (1964)). In order to inhibit coaggulation the blood was mixedwith 3.14% sodium citrate in a ratio by volume of 1:10.

Collagen-induced aggregation: The decrease in the optical density of theplatelet suspension was measured photometrically and recorded after theaddition of the aggregation-initiating substance. The speed ofaggregation was concluded from the angle of inclination of the densitycurve. The point on the curve at which there was maximum transmittancewas used to calculate the optical density.

The quantity of collagen used was as little as possible but sufficientto give an irreversible reaction curve. Standard commercial collagenproduced by Hormonchemie of Munich was used. Before the addition ofcollagen the plasma was incubated with the substance for 10 minutes at37° C.

From the measurements obtained, an EC₅₀ was determined graphically,relating to a 50% change in the optical density in terms of inhibitingaggregation.

The Table which follows contains the findings:

    ______________________________________                                                     Fibrinogen                                                                              Inhibition of                                          Substance    Binding test                                                                            platelet aggregation                                   (Example No.)                                                                              IC.sub.50 [nM]                                                                          EC.sub.50 [nM]                                         ______________________________________                                        1            1 800     9 900                                                  1(1)         45        1 500                                                  1(2)         96        320                                                    1(3)         190       1 700                                                  1(4)         3 900     >100 000                                               1(5)         6 100     32 000                                                 1(6)         17        70                                                     1(7)         2 400     10 000                                                 1(21)        31        620                                                    1(24)        470       1 100                                                  1(28)        52        390                                                    1(36)        37        100                                                    1(46)        11        40                                                     1(48)        210       1 100                                                  1(49)        26        140                                                    1(50)        45        290                                                    1(51)        3 600     13 000                                                 1(55)        860       60 000                                                 1(59)        150       350                                                    1(62)        13        40                                                     1(66)        9.1       50                                                     1(67)        30        60                                                     1(77)        4 900     8 000                                                  1(82)        17 000    29 000                                                 1(94)        310       400                                                    1(117)       230       5 400                                                  1(118)       170       460                                                    1(119)       210       730                                                    1(137)                 280                                                    1(138)       21        40                                                     1(139)       6.8       30                                                     1(140)       21        30                                                     1(141)       310       630                                                    1(143)       >10 000   22 000                                                 1(144)                 600                                                    1(145)       7.7       50                                                     1(146)       6.5       50                                                     1(147)       27        160                                                    1(148)       25        110                                                    1(149)       470       1 300                                                  1(150)       370       9 900                                                  1(153)       150       380                                                    1(154)       28        310                                                    1(156)       3 600     4 100                                                  2            6 000     12 000                                                 2(2)         25 000    630                                                    2(3)         18 000    3 100                                                  2(4)         15 000    42 000                                                 2(5)         5 600     25 000                                                 2(6)         240       160                                                    2(20)        5 700     690                                                    2(27)        2 500     490                                                    2(34)        7 400     350                                                    2(43)        420       100                                                    2(45)        370       280                                                    2(47)        32 000    >100 000                                               2(48)        22 000    >100 000                                               2(53)        4 500     200                                                    2(57)        640       320                                                    2(58)        4 700     140                                                    2(71)        13 000    14 000                                                 2(75)        8 000     27 000                                                 2(81)        19 000    1 500                                                  2(104)       7 100     2 100                                                  2(105)       28 000    1 100                                                  2(106)       2 700     6 600                                                  2(115)       530       80                                                     2(116)       59 000    49 000                                                 2(117)                 630                                                    2(118)       2 000     70                                                     2(119)       280       40                                                     2(122)                 1 200                                                  2(123)       3 100     70                                                     2(124)       1 200     130                                                    2(127)       5 600     18 000                                                 4(9)         2 600     9 500                                                  4(11)        45 000    2 300                                                  4(13)        32        310                                                    4(14)        41        200                                                    4(15)        42        300                                                    4(16)        1 500     1 900                                                  4(18)        48        210                                                    5            9 300     32 000                                                 5(1)         >100 000  20 000                                                 5(8)         8 000     31 000                                                 5(11)        5 700                                                            5(12)        3 700                                                            5(13)        >10 000   24 000                                                 5(18)        >10 000   8 060                                                  8            750       600                                                    8(1)         68 000    21 000                                                 8(2)         450       370                                                    8(3)         29 000    6 200                                                  8(5)         3 000     5 900                                                  11(11)                 210                                                    11(12)       43        30                                                     18           1 900     240                                                    18(5)        420       120                                                    30           4 400     8 300                                                  31           250       500                                                    31(1)        170       370                                                    ______________________________________                                    

Moreover, the compound of Example 5(18) for example inhibited thecollagen-induced thrombocyte aggregation ex vivo in Rhesus monkeys afteroral administration of 1 mg/kg for up to 8 hours.

The new compounds were well tolerated since the intravenousadministration of 30 mg/kg of the compound of Example 1(138) in mice didnot lead to the death of any of the three animals tested. Similarresults were obtained with the compounds of Examples 1(66) and 1(139) ata dose of 30 mg/kg, although in both cases one animal was sedated.

In view of their inhibitory effect on cell-cell and cell-matrixinteractions, the new cyclic urea derivatives of general formula I andthe physiologically acceptable addition salts thereof are suitable forcombating or preventing diseases in which smaller or larger clumps ofcells are produced or cell-matrix interactions are involved, e.g. incombating or preventing venous and arterial thrombosis, cerebro-vasculardiseases, pulmonary embolisms, cardiac infarct, arteriosclerosis,osteoporosis and tumour metastasis. They are also suitable as anaccompanying therapy in thrombolysis with fibrinolytics or vascularinterventions such as transluminal angioplasty or in the treatment ofshock, diabetes and inflammation.

For combating or preventing the above-mentioned diseases, the dose isbetween 0.1 μg and 20 mg/kg of body weight, preferably 1 μg to 10 mg/kgof body weight, in up to 4 doses per day. For this purpose, thecompounds of formula I prepared according to the invention may beformulated, optionally in conjunction with other active substances,together with one or more inert conventional carriers and/or diluents,e.g. with corn starch, lactose, glucose, microcrystalline cellulose,magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid,water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, stearyl alcohol, carboxymethylcellulose orfatty substances such as hard fat or suitable mixtures thereof, toproduce conventional galenic preparations such as plain or coatedtablets, capsules, powders, suspensions, solutions, sprays orsuppositories.

The Examples which follow are intended to illustrate the invention:

Example I

1-(3-Buten-1-yl)-3-(4'-cyano-4-biphenylyl)-imidazolin-2-one

9 g of 1-(4'-cyano-4-biphenylyl)-imidazolidin-2-one were dissolved at50° C. in 300 ml of dimethylformamide and 1.6 g of a 55% suspension ofsodium hydride in oil were added in batches thereto. The mixture wasstirred for a further 45 minutes, allowed to cool to ambient temperatureand, within 10 minutes, a solution of 4.16 ml of 1-bromo-3-butene in 15ml of dimethyl-formamide was added dropwise to the resulting suspensionand stirred for 3 days at ambient temperature. The reaction mixture waspoured onto 400 ml of water and the precipitate obtained was purified,after washing with water, by column chromatography on silica gel(eluant: methylene chloride/ethyl acetate=9:1).

Yield: 3.6 g (33% of theory),

Melting point: 171°-175° C.

R_(f) value: 0.54 (silica gel; cyclohexane/ethyl acetate=1:1)

The following compounds were obtained analogously:

(1)N-[4-(2-methoxycarbonyl-ethyl)-phenyl]-N-[2-(2,3,5,6-tetrahydro-2-pyranyloxy)-ethyl]-trifluoroacetamide

Heating for 20 hours to 70°-80° C.

R_(f) value: 0.47 (silica gel; diisopropylether)

(2)N-[4-(2-methoxycarbonyl-ethyl)-phenyl]-N-[3-(2,3,5,6-tetrahydro-2-pyranyloxy)-propyl]-trifluoroacetamide

Heating for 40 hours to 60° C.

R_(f) value: 0.49 (silica gel; diisopropylether)

(3) 1-methoxycarbonylmethyl-3H-benzimidazol-2-one

The base used was potassium tert.-butoxide and the solvent was methanol

R_(f) value: 0.89 (silica gel; methylene chloride/methanol=85:15)

(4)1-(3-buten-1-yl)-3-(4'-cyano-3'-fluoro-4-biphenylyl)-imidazolidin-2-one

(5)1-(3-buten-1-yl)-3-(3'-chloro-4,-cyano-4-biphenylyl)-imidazolidin-2-one

(6)1-(3-buten-1-yl)-3-(4'-cyano-3-methoxy-4-biphenylyl)-imidazolidin-2-one

(7)1-(3-buten-1-yl)-3-(4'-cyano-3-methylthio-4-biphenylyl)-imidazolidin-2-one

(8)1-(3-buten-1-yl)-3-(4'-cyano-2,3-dimethyl-4-biphenylyl)-imidazolidin-2-one

(9) 1-(3-buten-1-yl)-3-[4-(5-cyano-2-pyridyl)-phenyl]-imidazolidin-2-one

(10)1-(3-buten-1-yl)-3-[4-(5-cyano-2-pyrazinyl)-phenyl]-imidazolidin-2-one

(11)1-(3-buten-1-yl)-3-[4-(5-cyano-2-pyrimidinyl)-phenyl]-imidazolidin-2-one

(12)1-(3-buten-1-yl)-3-[6-(4-cyano-phenyl)-3-pyridazinyl]-imidazolidin-2-one

(13)1-(3-buten-1-yl)-3-[2-(4-cyano-phenyl)-5-pyrimidinyl]-imidazolidin-2-one

(14)N-[2-fluoro-4-(2-methoxycarbonyl-ethyl)-phenyl]-N-[2-(2,3,5,6-tetrahydro-2-pyranyloxy)-ethyl]-trifluoroacetamide

(15)N-[2-chloro-4-(2-methoxycarbonyl-ethyl)-phenyl]-N-[2-(2,3,5,6-tetrahydro-2-pyranyloxy)-ethyl]-trifluoroacetamide

(16)N-[2-methoxy-4-(2-methoxycarbonyl-ethyl)-phenyl]-N-[2-(2,3,5,6-tetrahydro-2-pyranyloxy)-ethyl]-trifluoroacetamide

The methyl 3-(4-amino-3-methoxy-phenyl)-propionate required for thetrifluoroacetylation with trifluoroacetic anhydride was obtained from3-(3-methoxy-phenyl)-propionic acid by nitrogenation, esterification andreduction with palladium/charcoal in methanol.

(17)N-[4-(2-methoxycarbonyl-ethyl)-2-methyl-phenyl]-N-[2-(2,3,5,6-tetrahydro-2-pyranyloxy)-ethyl]-trifluoro-acetamide

The 3-(4-amino-3-methyl-phenyl)-propionic acid was obtained from3-(3-methyl-phenyl)-propionic acid analogously to Example I (16).

(18)N-[4-(2-methoxycarbonyl-ethyl)-2-methylthio-phenyl]-N-[2-(2,3,5,6-tetrahydro-2-pyranyloxy)-ethyl]-trifluoroacetamide

The 3-(4-amino-3-methylthio-phenyl)-propionic acid was obtained from3-(4-amino-phenyl)-propionic acid analogously to Example III (10).

(19) 1-[6-(4-cyano-phenyl)-3-pyridazinyl]-imidazolidin-2-one

Prepared from imidazolidin-2-one and3-chloro-6-(4-cyano-phenyl)-pyridazine in dimethylsulphoxide

R_(f) value: 0.30 (silica gel; methylene chloride/methanol=19:1)

(20) 1-(4-cyano-phenyl)-3-(ethoxycarbonylmethyl)-imidazolidin-2-one

Melting point: 112°-115° C.

Example II

1-(4'-Cyano-4-biphenylyl)-imidazolidin-2-one

A solution of 5.7 g of potassium tert.-butoxide in 15 ml ofdimethylformamide was added dropwise at ambient temperature within 10minutes to a solution ofN-(2-chloroethyl)-N'-(4'-cyano-4-biphenylyl)-urea in 100 ml ofdimethylformamide. The mixture was stirred for one hour at ambienttemperature, poured onto 300 ml of water and the product precipitatedwas filtered off.

Yield: 13 g (98% of theory),

Melting point: above 200° C.

R_(f) value: 0.12 (silica gel; cyclohexane/ethyl acetate=1:1)

The following compounds were obtained analogously:

(1) 1-(4'-cyano-4-biphenylyl)-3,4,5,6-tetrahydro-1H-pyrimidin-2-one

Melting point: above 200° C.

R_(f) value: 0.44 (silica gel; methylene chloride/methanol=9:1)

(2) 1-(4'-cyano-3'-fluoro-4-biphenylyl)-imidazolidin-2-one

(3) 1-(3'-chloro-4'-cyano-4-biphenylyl)-imidazolidin-2-one

(4) 1-(4'-cyano-3-methoxy-4-biphenylyl)-imidazolidin-2-one

(5) 1-(4'-cyano-3-methylthio-4-biphenylyl)-imidazolidin-2-one

(6) 1-(4'-cyano-2,3-dimethyl-4-biphenylyl)-imidazolidin-2-one

(7) 1-[4-(5-cyano-2-pyridyl)-phenyl]-imidazolidin-2-one

(8) 1-[4-(5-cyano-2-pyrazinyl)-phenyl]-imidazolidin-2-one

(9) 1-[4-(5-cyano-2-pyrimidinyl)-phenyl]-imidazolidin-2-one

(10) 1-[2-(4-cyano-phenyl)-5-pyrimidinyl]-imidazolidin-2-one

(11) 1-[2-(4'-cyano-4-biphenylyl)-ethyl]-imidazolidin-2-one

(12)1-(1-benzyl-4-piperidinyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(13) 1-(4-cyano-phenyl)-imidazolidin-2-one

Potassium carbonate was used as base, heating to 60° C. for 6 hours.

Melting point: 172°-175° C.

R_(f) value: 0.23 (silica gel; cyclohexane/ethyl acetate=1:3)

(14)1-(4-cyano-phenyl)-3-[4-[2-(dimethoxy-phosphoryl)-ethyl]-phenyl]-imidazolidin-2-one

Prepared analogously to Example 14.

(15) 1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Melting point: 171°-172° C.

(16)2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4-dihydro-2H,5H-thiadiazol-1,1-dioxide

Melting point: 110°-112° C.

(17)1-(4-bromo-2-methyl-phenyl)-3-[4-(2-methoxy-carbonyl-ethyl)-phenyl]-imidazolidin-2-one

Prepared fromN-(4-bromo-2-methyl-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-ureavia the mesylate and iodide without purification of these products.

Melting point: 164°-166° C.

Example III

N-(2-Chloroethyl)-N'-(4'-cyano-4-biphenylyl)-urea

1.1 ml of 2-chloroethyl-isocyanate was added to a solution of4-amino-4'-cyano-biphenyl in 15 ml of dimethylformamide and the mixturewas stirred for 3 hours at ambient temperature. The reaction mixture waspoured onto 50 ml of water, stirred for 3 hours and the productprecipitated was filtered off.

Yield: 1.4 g (91% of theory),

R_(f) value: 0.40 (silica gel; cyclohexane/ethyl acetate=1:1)

The following compounds were obtained analogously:

(1) N-(4'-cyano-4-biphenylyl)-N-(2,2-diethoxy-ethyl)-N^('-)(2-ethoxycarbonyl-ethyl)-urea

The work was done in dioxane as solvent in the presence ofethyl-diisopropylamine at 50° C. Purification was carried out bychromatography on silica gel (eluant: cyclohexane/ethyl acetate=1:1).

The ethyl 3-isocyanato-propionate used was obtained fromβ-alanine-ethylester-hydrochloride and phosgene in toluene as thesolvent.

Melting point: 85°-88° C.

R_(f) value: 0.28 (silica gel; cyclohexane/ethyl acetate=1:1)

(2)N-(tert.butyloxycarbonylmethyl)-N-(4'-cyano-4-biphenylyl)-N'-(2-ethoxycarbonyl-ethyl)-urea

Prepared analogously to Example III (1).

Melting point: 118°-120° C. (from tert.butyl-methylether)

R_(f) value: 0.46 (silica gel; cyclohexane/ethyl acetate=1:1)

(3)N-(4'-cyano-4-biphenyl)-N-[3-(2,3,5,6-tetrahydro-2-pyranyloxy)-propyl]-N'-(2-ethoxycarbonyl-ethyl)-urea

Prepared analogously to Example III (1).

R_(f) value: 0.49 (silica gel; cyclohexane/ethyl acetate=1:3)

(4) N-(3-chloropropyl)-N'-(4'-cyano-4-biphenylyl)-urea

R_(f) value: 0.39 (silica gel; cyclohexane/ethyl acetate=1:1)

(5)N-(4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

Solvent: dioxane

R_(f) value: 0.32 (silica gel; cyclohexane/ethyl acetate=3:7)

(6)N-(4-cyano-phenyl)-N'-(3-hydroxy-propyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

Solvent: dioxane

Melting point: 86°-89° C.

R_(f) value: 0.27 (silica gel; cyclohexane/ethyl acetate=3:7)

(7) N-(2-chloroethyl)-N'-(4'-cyano-3'-fluoro-4-biphenylyl)-urea

The 4-amino-4'-cyano-3'-fluoro-biphenyl used as starting material wasobtained from 4-bromo-2-fluoro-benzonitrile by reacting with phenylboronic acid in the presence of palladium(II)acetate andtris-o-tolyl-phosphine with subsequent nitrogenation and reduction ofthe nitro group with 5% palladium charcoal in ethyl acetate.

(8) N-(3'-chloro-4'-cyano-4-biphenylyl)-N'-(2-chloroethyl)-urea

The 4-amino-3'-chloro-4'-cyano-biphenyl used as starting material wasobtained analogously to Example III (7).

(9) N-(2-chloroethyl)-N'-(4'-cyano-3-methoxy-4-biphenylyl)-urea

The 4-amino-4'-cyano-3-methoxy-biphenyl used as starting material wasobtained analogously to Example III (7).

(10) N-(2-chloroethyl)-N'-(4'-cyano-3-methylthio-4-biphenylyl)-urea

The starting material 4-amino-4'-cyano-3-methylthio-biphenyl wasobtained from 4'-amino-4-biphenyl-carboxylic acid by reacting withammonium rhodanide and bromine in acetic acid, saponifying the resulting2-amino-benzothiazole derivative with dilute potassium hydroxidesolution, methylating the mercapto group, protecting the amino group bymeans of the phthalyl derivative, converting the carboxyl group into acyano group (via the acid chloride and the acid amide with subsequentdehydration with phosphorusoxychloride/pyridine) and cleaving thephthalyl group with aqueous methylamine solution.

(11) N-(2-chloroethyl)-N'-(4'-cyano-2,3-dimethyl-4-biphenylyl)-urea

The starting material 4-amino-4'-cyano-2,3-dimethyl-biphenyl wasobtained analogously to Example III (7).

(12) N-(2-chloroethyl)-N'-[4-(5-cyano-2-pyridyl)-phenyl]-urea

The starting material 2-(4-amino-phenyl)-5-cyano-pyridine was obtainedanalogously to Example III (7), using4-(2,2,5,5-tetramethyl-1-aza-2,5-disila-1-cyclopentanyl)-phenyl boronicacid (prepared from4-(2,2,5,5-tetramethyl-1-aza-2,5-disila-l-cyclopentanyl)-phenyl-lithiumand trimethoxyborane) and hydrolytically removing the silyl protectinggroup.

(13) N-(2-chloroethyl)-N'-[4-(5-cyano-2-pyrazinyl)-urea

The starting material 2-(4-amino-phenyl)-5-cyano-pyrazine was obtainedfrom 4-nitro-phenylglyoxal by condensation with glycinamide, treatingthe product with phosphorusoxytribromide, bromine exchange withcopper(I)cyanide and subsequent reduction of the nitro group analogouslyto Example III (7).

(14) N-(2-chloroethyl)-N'-[4-(5-cyano-2-pyrimidinyl)-phenyl]-urea

The starting material 2-(4-amino-phenyl)-5-cyano-pyrimidine was obtainedfrom 4-nitro-benzamidine and 3-dimethylamino-2-formyl-acrylonitrile withsubsequent reduction of the nitro group analogously to Example III (7).

(15) N-(2-chloroethyl)-N'-[2-(4-cyano-phenyl)-5-pyrimidinyl]-urea

The starting material 5-amino-2-(4-cyano-phenyl)-pyrimidine was obtainedby first condensing ethyl 4-amidino-benzoate with diethylmalonate in thepresence of sodium methoxide, nitrogenating the resultingpyrimidinedione and chlorinating with phosphorus oxychloride/phosphoruspentachloride and catalytically hydrogenating the product. The resulting5-amino-2-(4-ethoxycarbonyl-phenyl)-pyrimidine was converted into theaminocarbonyl compound and dehydrated with phosphorusoxychloride/pyridine to obtain the nitrile.

(16)N-[4-(4-cyano-phenyl)-cyclohexyl]-N-(2,2-diethoxyethyl)-N'-(2-ethoxycarbonyl-ethyl)-urea

The starting materialN-[4-(4-cyano-phenyl)-cyclohexyl]-N-(2,2-diethoxy-ethyl)-amine wasobtained by reductive amination of 4-(4-cyano-phenyl)-cyclohexanone with2,2-diethoxyethylamine in the presence of sodium cyanoboro-hydride.

(17) N-(2-chloroethyl)-N'-[2-(4'-cyano-4-biphenylyl)-ethyl]-urea

The starting material 2-(4'-cyano-4-biphenylyl)-ethylamine was obtainedfrom 2-(4'-cyano-4-biphenylyl)-ethylbromide and potassium phthalimideand subsequently reacted with aqueous methylamine solution.

(18)N-(4-cyano-3-fluoro-phenyl)-N'-(2-hydroxy-ethyl)-N,-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

The 4-amino-2-fluoro-benzonitrile from which the isocyanate was obtainedanalogously to Example III (1) was obtained from2-fluoro-4-nitro-benzoic acid by conversion into the acid amide,cleaving the water by heating with phosphorus oxychloride/pyridine andreduction with hydrogen in the presence of 5% palladium/charcoal inethyl acetate.

(19)N-(3-chloro-4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea(The isocyanate was prepared analogously to Example III (1))

(20)N-(4-cyano-2-methylthio-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

The 4-amino-3-methylthio-benzonitrile which was converted into theisocyanate analogously to Example III (1) was obtained from4-amino-3-methylthio-benzoic acid analogously to Example III (10).

(21)N-(4-cyano-2-methyl-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea(The isocyanatewasprepared analogously to Example III (1))

(22)N-(4-cyano-2-methoxy-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

The starting material 4-amino-3-methoxy-benzonitrile, whichwasconvertedinto the isocyanate analogously to Example III (1),wasobtained from3-methoxy-4-nitro-benzoic acid analogously to Example III (18)

(23)N-(4-cyano-phenyl)-N'-[2-fluoro-4-(2-methoxycarbonyl-ethyl)-phenyl]-N'-(2-hydroxy-ethyl)-urea

(24)N-[2-chloro-4-(2-methoxycarbonyl-ethyl)-phenyl]-N-(2-hydroxy-ethyl)-N'-(4-cyano-phenyl)-urea

(25)N-(4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-[2-methoxy-4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(26)N-(4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-2-methyl-phenyl]-urea

(27)N-(4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-2-methylthio-phenyl]-urea

(28)N-(4-cyano-phenyl)-N-(2-hydroxy-ethyl)-N'-[5-(2-methoxycarbonyl-ethyl)-2-pyridyl]-urea

(29)N-(4-cyano-phenyl)-N-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-cyclohexyl]-urea

(30)N-(4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-(4-methoxycarbonylmethyloxy-phenyl)-urea

(31)N-(4-tert.butyloxy-carbonylmethylthio-phenyl)-N-(2-hydroxy-ethyl)-N'-(4-cyano-phenyl)-urea

Melting point: 111°-114° C.

(32)N-(4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(3-methoxycarbonyl-2-methyl-2-propyl)-phenyl]-urea

Melting point: 113°-116° C.

(33)N-(4-cyano-phenyl)-N'-[4-[2-(dimethoxy-phosphoryl)-ethyl]-phenyl]-N'-(2-hydroxy-ethyl)-urea

(34) N-(4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-[2-(4-ethoxycarbony1-phenyl)-ethyl]-urea

(35)N-(4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethenyl)-phenyl]-urea

(36)N-(5-cyano-2-pyridyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(37)N-(1-benzyl-4-piperidinyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(38)N-(4-cyano-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(3-methoxycarbonyl-propyl)-phenyl]-urea

(39)N-(4-cyano-phenyl)-N'-(2,2-diethoxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

R_(f) value: 0.60 (silica gel; cyclohexane, ethyl acetate=1:1)

(40) N-(2-chloroethyl)-N'-(4-cyano-phenyl)-urea

R_(f) value: 0.29 (silica gel; methylene chloride, methanol=40:1,developed three times)

(41)N-(4-cyano-phenyl)-N'-(2,2-dimethoxy-ethyl)-N'-[2-(4-methoxycarbonyl-phenyl)-ethyl]-urea

Melting point: 109°-110° C.

(42)N-(4-cyano-phenyl)-N'-(2-hydroxy-propyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

The work was done in dioxane without an auxiliary base.

R_(f) value: 0.40 (silica gel; ethyl acetate/cyclohexane=2:1)

(43)N-acetylamino-N-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-N'-(4-cyano-phenyl)-urea

The work was done in dioxane without an auxiliary base.

Melting point: 126°-128° C.

(44)N-(4-cyano-phenyl)-N'-(2-hydroxy-propyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

The work was done in dioxane without an auxiliary base.

R_(f) value: 0.25 (silica gel; cyclohexane/ethyl acetate=1:1)

(45)N-(4-cyano-phenyl)-N'-formylamino-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

The work was done in dioxane without an auxiliary base.

Melting point: 166°-168° C.

(46)N-(4-cyano-phenyl)-N-formylamino-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

Melting point: 180°-183° C.

(47)N-acetylamino-N-(4-cyano-phenyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

Melting point: 153°-155° C.

(48) N-(2-chloro-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

Melting point: 124°-125° C.

(49)N-[1-(4-cyano-phenyl)-4-piperidinyl]-N-(2,2-dimethoxyethyl)-N'-(2-ethoxycarbonyl-ethyl)-urea

Melting point: 90°-92° C.

(50)N-(4-cyano-phenyl)-N-(propionylamino)-N'-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-urea

Melting point: 149°-153° C.

(51)N-(4-cyano-phenyl)-N'-(2,2-diethoxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethenyl)-phenyl]-urea

R_(f) value: 0.68 (silica gel; cyclohexane/ethyl acetate=1:1)

(52)N-(4-cyano-phenyl)-N'-[4-(2-dibenzylamino-2-methoxycarbonyl-ethyl)-phenyl]-N'-(2,2-diethoxy-ethyl)-urea

R_(f) value: 0.52 (silica gel; cyclohexane/ethyl acetate=2:1)

(53)N-[4-(2-tert.butyloxycarbonylamino-2-methoxycarbonyl-ethyl)-phenyl]-N'-(4-cyano-phenyl)-N'-(2,2-diethoxy-ethyl)-urea

R_(f) value: 0.15 (silica gel; cyclohexane/ethyl acetate=2:1)

(54)N-(4-bromo-2-methyl-phenyl)-N'-(2-hydroxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

The work was done in dioxane without an auxiliary base.

Melting point: 101°-104° C.

Example IV

N-(4'-Cyano-4 -biphenylyl)-N-(2,2-diethoxy-ethyl)-amine

A mixture of 10 g of 4-amino-4'-cyano-biphenyl, 8.3 ml ofbromoacetaldehyde-diethylacetal, 13.9 ml of ethyl-diisopropylamine and20 ml of dimethylformamide was stirred for 16 hours at a bathtemperature of 160° C. It was evaporated to dryness and the residue waspurified by column chromatography over silica gel (eluant:cyclohexane/ethyl acetate=2:1).

Yield: 3 g (19% of theory),

Melting point: 88°-90° C.

R_(f) value: 0.54 (silica gel; cyclohexane/ethyl acetate=2:1)

The following compounds were obtained analogously:

(1) N-(tert.butyloxycarbonyl-methyl)-N-(4'-cyano-4-biphenylyl)-amine

The work was done at ambient temperature, recrystallising fromcyclohexane/ethyl acetate=20:2

Melting point: 151°-153° C.

R_(f) value: 0.76 (silica gel; cyclohexane/ethyl acetate=1:1)

(2)N-(4'-cyano-4-biphenylyl)-N-[3-(2,3,5,6-tetrahydro-2-pyranyl)-propyl]-amin

The work was done at 110° C.

Melting point: 111°-113° C.

R_(f) value: 0.65 (silica gel; cyclohexane/ethyl acetate=1:1)

(3) N-(2,2-diethoxy-ethyl)-N-[4-(2-methoxycarbonyl-ethyl)-phenyl]-amine

R_(f) value: 0.35 (silica gel; cyclohexane/ethyl acetate=8:2)

(4) N-(2,2-diethoxy-ethyl)-N-[2-(4-methoxycarbonyl-phenyl)-ethyl]-amine

The starting materials used were 2,2-dimethoxy-ethylamine and methyl4-(2-chloro-ethyl)-benzoate.

Heating was carried out for 72 hours to 50° C.

R_(f) value: 0.46 (silica gel; ethyl acetate/methanol=4:1)

(5) N-(4-cyano-phenyl)-glycine-tert.-butylester

Melting point: 110°-112° C.

(6) methyl 4-[(2,2-diethoxy-ethyl)-amino]-cinnamate

R_(f) value: 0.79 (silica gel; cyclohexane/ethyl acetate=1:1)

(7) methyl2-dibenzylamino-3-[4-[(2,2-diethoxy-ethyl)-amino]-phenyl]-propionate

R_(f) value: 0.59 (silica gel; cyclohexane/ethyl acetate=2:1)

(8) methyl 2-dibenzylamino-3-(4-nitro-phenyl)-propionate

The work was done in methanol.

R_(f) value: 0.65 (silica gel; cyclohexane/ethyl acetate=2:1)

(9) methyl2-tert.butyloxycarbonylamino-3-[4-(2,2-diethoxy-ethylamino)-phenyl]-propionate

R_(f) value: 0.45 (silica gel; cyclohexane/ethyl acetate=2:1)

Example V

N-(4'-Cyano-4-biphenylyl)-N-(3-methanesulphonyloxy-propyl)-N'-(2-ethoxycarbonyl-ethyl)-urea

A mixture of 2 g ofN-(4'-cyano-4-biphenylyl)-N-(3-hydroxypropyl)-N'-(2-ethoxycarbonyl-ethyl)-urea,0.45 ml of methanesulphonyl chloride and 15 ml of methylene chloride wascooled to 0° C. and within 15 minutes mixed with 0.8 ml oftriethylamine. The mixture was stirred for one hour at 0° C. and afurther hour at ambient temperature, 25 ml of methylene chloride wereadded and the mixture was extracted with water. It was evaporated downand the residue was crystallised by triturating withtert.-butylmethylether.

Yield: 1.9 g (79% of theory),

R_(f) value: 0.47 (silica gel; ethyl acetate)

The following compounds were obtained analogously:

(1)N-(4-cyano-phenyl)-N'-(2-methanesulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

R_(f) value: 0.39 (silica gel; cyclohexane/ethyl acetate=3:7)

(2)N-(4-cyano-phenyl)-N'-(3-methanesulphonyloxy-propyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

R_(f) value: 0.43 (silica gel; cyclohexane/ethyl acetate=3:7)

(3)N-(4-cyano-3-fluoro-phenyl)-N'-(2-methane-sulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(4)N-(3-chloro-4-cyano-phenyl)-N'-(2-methane-sulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(5)N-(3-cyano-2-methylthio-phenyl)-N'-(2-methane-sulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(6)N-(4-cyano-2-methyl-phenyl)-N'-(2-methane-sulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(7)N-(4-cyano-2-methoxy-phenyl)-N'-(2-methane-sulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(8)N-(4-cyano-phenyl)-N'-[2-fluoro-4-(2-methoxy-carbonyl-ethyl)-phenyl]-N'-(2-methanesulphonyloxy-ethyl)-urea

(9)N-[2-chloro-4-(2-methoxycarbonyl-ethyl)-phenyl]-N-(2-methanesulphonyloxy-ethyl)-N'-(4-cyano-phenyl)-urea

(10)N-(4-cyano-phenyl)-N'-(2-methanesulphonyloxy-ethyl)-N'-[2-methoxy-4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(11)N-(4-cyano-phenyl)-N'-(2-methanesulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-2-methyl-phenyl]-urea

(12)N-(4-cyano-phenyl)-N'-(2-methanesulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-2-methylthio-phenyl]-urea

(13)N-(4-cyano-phenyl)-N-(2-methanesulphonyloxy-ethyl)-N'-[5-(2-methoxycarbonyl-ethyl)-2-pyridyl]-urea

(14)N-(4-cyano-phenyl)-N-(2-methanesulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-cyclohexyl]-urea

(15)N-(4-cyano-phenyl)-N'-(2-methanesulphonyloxy-ethyl)-N'-(4-methoxycarbonylmethyloxy-phenyl)-urea

(16)N-(4-tert.butyloxycarbonylmethylthio-phenyl)-N-(2-methanesulphonyloxy-ethyl)-N'-(4-cyano-phenyl)-urea

R_(f) value: 0.35 (silica gel; methylene chloride/ethyl acetate=95:5)

(17)N-(4-cyano-phenyl)-N'-(2-methanesulphonyloxy-ethyl)-N'-[4-(3-methoxycarbonyl-2-methyl-2-propyl)-phenyl]-urea

R_(f) value: 0.57 (silica gel; cyclohexane/ethyl acetate

(18)N-(4-cyano-phenyl)-N'-[4-[2-(dimethoxy-phosphoryl)-ethyl]-phenyl]-N'-(2-methanesulphonyloxy-ethyl)-urea

(19)N-(4-cyano-phenyl)-N'-[2-(4-ethoxycarbonyl-phenyl)-ethyl]-N'-(2-methanesulphonyloxy-ethyl)-urea

(20)N-(4-cyano-phenyl)-N'-(2-methanesulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethenyl)-phenyl]-urea

(21)N-(5-cyano-2-pyridyl)-N'-(2-methanesulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(22)N-(1-benzyl-4-piperidinyl)-N'-(2-methane-sulphonyloxy-ethyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-urea

(23)N-(4-cyano-phenyl)-N'-(2-methanesulphonyloxy-ethyl)-N'-[4-(3-methoxycarbonyl-propyl)-phenyl]-urea

(24)1-(4-cyano-phenyl)-3-(2-methanesulphonyloxy-ethyl)-imidazolidin-2-one

Melting point: 98°-100° C.

(25)N'-(4-cyanomethyl-phenyl)-N'-(2-methane-sulphonyloxy-ethyl)-N'-(4-methoxycarbonylmethyl-phenyl)-urea

R_(f) value: 0.19 (silica gel; cyclohexane/ethyl acetate=6:4)

Example VI

N-(4'-Cyano-4-biphenylyl)-N-(3-hydroxy-propyl)-N'-(2-ethoxycarbonyl-ethyl)-urea

4.1 g ofN-(4'-cyano-4-biphenylyl)-N-[3-(2,3,5,6-tetrahydro-2-pyranyloxy)-propyl]-N'-(2-ethoxycarbonyl-ethyl)-ureawere dissolved in 15 ml of ethanol, 0.2 ml of ethereal hydrochloric acidwere added and the mixture was stirred for 2 hours at ambienttemperature. It was evaporated to dryness, taken up in 200 ml ofmethylene chloride, extracted with 10% sodium bicarbonate solution andthe organic phase was evaporated to dryness. The residue was purified bycolumn chromatography on silica gel (eluant: ethyl acetate).

Yield: 2.1 g (64% of theory),

Melting point: 120°-122° C.

R_(f) value: 0.36 (silica gel; ethyl acetate)

The following compound was obtained analogously:

(1) 1-(4-cyano-phenyl)-piperidin-4-one

Prepared from the corresponding ethylene ketal with pyridiniumtoluenesulphonate in acetone/water at 100° C.

Melting point: 102°-104° C.

Example VII

N-(2-Hydroxy-ethyl)-N-[4-(2-methoxycarbonyl-ethyl)-phenyl]-amine

1.5 g ofN-[4-(2-methoxycarbonyl-ethyl)-phenyl]-N-[2-(2,3,5,6-tetrahydro-2-pyranyloxy)-ethyl]-trifluoro-acetamidewere stirred for 2 hours in a mixture of 20 ml of methanol and 2.5 ml of4N sodium hydroxide solution at ambient temperature. Then the mixturewas neutralised with glacial acetic acid, evaporated down and all thewater was eliminated by boiling with toluene using a water separator.The residue was concentrated by evaporation, taken up in 20 ml ofmethanol, 2 ml of methanolic hydrochloric acid were added and theresulting mixture was left to stand for 16 hours at ambient temperature.The precipitate was filtered off, the filtrate was evaporated down andstirred with 10 ml of methylene chloride and 5 ml of 0.1N sodiumhydroxide solution. The organic phase was evaporated down and theremaining oil was used directly for further processing.

Yield: 0.65 g (78% of theory),

R_(f) value: 0.43 (silica gel; cyclohexane/ethyl acetate=3:7)

The following compounds were obtained analogously:

(1) N-(3-hydroxy-propyl)-N-[4-(2-methoxycarbonyl-ethyl)-phenyl]-amine

R_(f) value: 0.44 (silica gel; cyclohexane/ethyl acetate=3:7)

(2)N-[2-fluoro-4-(2-methoxycarbonyl-ethyl)-phenyl]-N-(2-hydroxy-ethyl)-amine

(3)N-[2-chloro-4-(2-methoxycarbonyl-ethyl)-phenyl]-N-(2-hydroxy-ethyl)-amine

(4)N-(2-hydroxy-ethyl)-N-[2-methoxy-4-(2-methoxy-carbonyl-ethyl)-phenyl]-amine

(5)N-(2-hydroxy-ethyl)-N-[4-(2-methoxycarbonyl-ethyl)-2-methyl-phenyl]-amine

(6)N-(2-hydroxy-ethyl)-N-[4-(2-methoxycarbonyl-ethyl)-2-methylthio-phenyl]-amine

Example VIII

3-(4-Cyano-phenyl)-3H-imidazo[4,5-b]pyridin-2-one

0.21 g of 3-amino-2-[(4-cyano-phenyl)-amino]-pyridine and 0.26 g ofN-ethyl-diisopropylamine were dissolved in 4.5 ml of methylene chlorideand, whilst cooling with ice, 0.5 ml of a 20% solution of phosgene intoluene was added in batches and resulting mixture was stirred for 1.5hours at ambient temperature. A further 0.3 ml of the phosgene solutionwas added and stirring was continued for 20 minutes. The precipitateobtained was filtered off and washed with methylene chloride.

Yield: 0.17 g (72% of theory),

R_(f) value: 0.47 (silica gel; methylene chloride/methanol=19:1)

The following compound was obtained analogously:

(1) 3-(4'-cyano-4-biphenylyl)-3H-imidazo[4,5-b]pyridin-2-one

R_(f) value: 0.44 (silica gel; methylene chloride/methanol=9:1)

Example IX

1-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-3-(4-piperidinyl)-imidazolidin-2-one

Prepared by treating1-(1-benzyloxycarbonyl-4-piperidinyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onewith hydrogen at 3 bars in the presence of 5% palladium/charcoal inmethanol.

Example X

2-[(2-Ethoxycarbonyl-ethyl)-aminosulphonyloxy]-phenol

1.54 g of .-alanine ethylester-hydrochloride and 1.9 g of1,2-sulphonyldioxybenzene were dissolved in 10 ml of dimethylformamide,1.55 g of ethyl-diisopropylamine were added and the mixture was stirredfor two hours at ambient temperature. The solvent was distilled off invacuo and the residue was purified by column chromatography (silica gel;eluant: cyclohexane/ethyl acetate=8:2)

Yield: 1.4 g (48% of theory)

R_(f) value: 0.31 (silica gel; cyclohexane/ethyl acetate=7:3)

The following compound was obtained analogously:

(1) 4-cyano-4'-[(2-ethoxycarbonyl-ethyl)-aminosulphonylamino]-biphenyl

The work was done without an auxiliary base and by heating for 15 hoursto 80° C.

Melting point: 103°-105° C.

R_(f) value: 0.21 (silica gel; cyclohexane/ethyl acetate=7:3)

Example XI

Methyl 3-[4-[(2-hydroxy-propyl)-amino]-phenyl]-propionate

6 g of methyl 3-(4-amino-phenyl)-propionate hydrochloride were suspendedin methylene chloride and 27.9 ml of 1N sodium hydroxide solution wereadded. The organic phase was separated off, the mixture was extractedtwice more with methylene chloride and the combined organic phases wereevaporated down. The residue was taken up in 50 ml of methanol and 1.9ml of propylene oxide and 2 ml of water were added. It was stirred for48 hours at ambient temperature, evaporated down and purified oversilica gel (eluant: cyclohexane/ethyl acetate=1:1).

Yield: 3.5 g (54% of theory),

R_(f) value: 0.40 (silica gel; cyclohexane/ethyl acetate=1:1)

Example XII

4-[(2-Hydroxy-propyl)-amino]-benzonitrile

12.1 g of 4-fluoro-benzonitrile, 7.5 g of 2-hydroxy-propylamine and 17.4ml of N-ethyl-diisopropylamine were heated together to 100° C. for 2.5hours. The mixture was poured onto 250 ml of water, extracted five timeswith 50 ml of ethyl acetate and the combined organic phases wereevaporated down. The product remaining was purified by columnchromatography (silica gel; eluant: ethyl acetate) and crystallised bytriturating with a 1:1-mixture of tert.butyl-methylether and petroleumether.

Yield: 2.2 g (13% of theory),

Melting point: 70°-73° C.

The following compound was obtained analogously:

(1) 1-(4-cyano-phenyl)-4,4-ethylenedioxy-piperidine

Melting point: 136°-138° C.

Example XIII

1-[4-(2-Methoxycarbonyl-ethyl)-cyclohexyl]-imidazolidin-2-one

2 g of 1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one werehydrogenated in a mixture of 20 ml of methanol and 30 ml of glacialacetic acid in the presence of a platinum/rhodium catalyst with hydrogenat 5 bars at 50° C. for 50 minutes. The catalyst was filtered off, thefiltrate was evaporated down and the remaining product was used withoutfurther purification.

Yield: 2.03 g (100% of theory),

R_(f) value: 0.29 (silica gel; ethyl acetate/cyclohexane=9:1)

Example XIV

Methyl 3-[4-[(2-chloro-ethyl)-aminosulphonylamino]-phenyl]-propionate

At -30° C., 6.7. g of N-(2-chloroethyl)-N-chlorosulphonyl-amine,dissolved in 10 ml of methylene chloride, were added dropwise to asolution of 8.6 g of methyl 3-(4-amino-phenyl)-propionate hydrochlorideand 12.9 g of N-ethyl-diisopropylamine in 40 ml of methylene chloride.The mixture was stirred for a further 2 hours, whilst coming up toambient temperature. The reaction mixture was washed with water,evaporated down and purified by column chromatography (silica gel;cyclohexane/ethyl acetate=7:3).

Yield: 8.3 g (65% of theory),

Melting point: 97°-99° C.

The following compound was obtained analogously:

(1) Tert.butylester of N-(4-cyano-phenyl)-N-methoxycarbonyl-glycinePotassium carbonate and 4-dimethylamino-pyridine in chloroform wereused.

R_(f) value: 0.42 (silica gel; cyclohexane/ethyl acetate=7:3)

Example XV

1-(4-Cyano-phenyl)-4-[(2,2-dimethoxy-ethyl)-amino]-piperidine

11 g of 1-(4-cyano-phenyl)-piperidin-4-one were dissolved in 90 ml ofacetonitrile, then mixed with 10 ml of water and 6.9 g ofaminoacetaldehyde-dimethylacetal. 18.3 ml of 3N hydrochloric acid wereadded dropwise and 4.5 g of sodium cyanoborohydride were added. After 20minutes' stirring at ambient temperature the acetonitrile was evaporatedoff in vacuo and the residue was extracted with ethyl acetate. Theresidue remaining after evaporation of the ethyl acetate phases waspurified by chromatography on silica gel (eluant: methylenechloride/methanol=100:3).

Yield: 10.8 g (74% of theory),

R_(f) value: 0.34 (silica gel; methylene chloride/methanol/concentratedammonia=95:5:0.1)

The following compounds were obtained analogously:

(1) Methyl 3-[4-[(2-hydroxy-ethyl)-amino]-phenyl]-3-methyl-butyrate

R_(f) value: 0.35 (silica gel; cyclohexane/ethyl acetate=1:1)

(2) Methyl 4-[(2-hydroxy-ethyl)-amino]-phenylacetate

R_(f) value: 0.25 (silica gel; cyclohexane/ethyl acetate=1:1)

Example XVI

N-(4-Cyano-phenyl)-N-methoxycarbonyl-glycine-[4-(2-methoxycarbonyl-ethyl)-anilide]

A mixture of 3.7 g of N-(4-cyano-phenyl)-N-methoxycarbonyl-glycine, 2.4g of i-hydroxy-benzotriazole, 150 ml of tetrahydrofuran, 2.81 g ofmethyl 3-(4-amino-phenyl)-propionate, 4.2 g ofN,N'-dicyclohexylcarbodiimide and 1.62 g of triethylamine was stirredfor 64 hours at ambient temperature. The precipitate formed was filteredoff, the filtrate was evaporated down and the residue was purified bycolumn chromatography over silica gel (eluant: cyclo-hexane/ethylacetate=1:1 to 2:3).

Yield: 5.5 g (88% of theory),

Melting point: 100°-110° C.

The following compound was obtained analogously:

(1) N-(4-cyano-phenyl)-N'-propionyl-hydrazine

Carbonyldiimidazole in tetrahydrofuran was used.

Melting point: 143°-145° C.

Example XVII

N-(4-Cyano-phenyl)-N-methoxycarbonyl-glycine

7 g of the tert.butylester ofN-(4-cyano-phenyl)-N-methoxycarbonyl-glycine were dissolved in 70 ml ofmethylene chloride and a solution of 18 ml of trifluoroacetic acid in 18ml of methylene chloride was added dropwise thereto. The mixture wasleft to stand for 16 hours at ambient temperature, evaporated down, theresidue was taken up in tert.butylmethylether, washed with water and theorganic phase was evaporated down. The residue was briefly boiled with50 ml of diethylether and, after cooling in the ice bath, filtered off.Another fraction can be obtained from the mother liquors.

Yield: 3.85 g (68% of theory),

Melting point: 134°-137° C.

Example XVIII

Methyl 3-(4-amino-phenyl)-2-dibenzylamino-propionate

5.35 g of methyl 2-dibenzylamino-3-(4-nitro-phenyl)-propionate,dissolved in 100 ml of methanol, were treated with hydrogen under apressure of 5 bars in the presence of 1 g of Raney nickel at ambienttemperature for 8 hours. The catalyst was filtered off, the filtrate wasevaporated down and the crude product remaining was used withoutpurification.

Yield: 4.9 g (92% of theory),

R_(f) value: 0.45 (silica gel; cyclohexane/ethyl acetate=2:1)

The following compounds were obtained analogously:

(1) 3-amino-2-[(4-cyano-phenyl)-amino]-pyridine

The work was done in a 3:1 mixture of ethyl acetate and methanol with10% palladium/charcoal

R_(f) value: 0.62 (silica gel; methylene chloride/methanol=9:1)

(2) 3-amino-2-[(4'-cyano-4-biphenylyl)-amino]-pyridine

The work was done in a 3:1 mixture of ethyl acetate and methanol with10% palladium/charcoal

R_(f) value: 0.66 (silica gel; methylene chloride/methanol=19:1)

Example XIX

1-(4-Cyano-phenyl)-3-(2-hydroxy-ethyl)-imidazolidin-2-one

0.71 g of lithium borohydride were added in batches to a solution of 8.8g of 1-(4-cyano-phenyl)-3-(ethoxycarbonylmethyl)-imidazolidin-2-one in500 ml of tetrahydrofuran with stirring at ambient temperature. Themixture was stirred for 1 hour at ambient temperature and for 2 hours at60° C., then after cooling in an ice bath 16.5 ml of 2N hydrochloricacid were added and the resulting mixture was evaporated down in vacuo.The residue was digested with 50 ml of methanol, the methanol phase wasevaporated down and the residue was purified over silica gel (eluant:ethyl acetate/methanol=9:1)

Yield: 5.0 g (67% of theory),

Melting point: 112°-114° C.

Example XX

N-(4-Cyanomethyl-phenyl)-N'-(2-hydroxy-ethyl)-N'-(4-methoxycarbonylmethyl-phenyl)-urea

1.46 g of carbonyldiimidazole and 1.04 g of imidazole were dissolved in20 ml of tetrahydrofuran. The mixture was cooled to 0° C. and 1.18 g of4-amino-benzylcyanide were added. After about 3 minutes a solution ofmethyl 4-[(2-hydroxy-ethyl)-amino]-phenylacetate in 7 ml oftetrahydrofuran was rapidly added dropwise, the ice cooling was takenaway and the mixture was stirred for 16 hours at ambient temperature (aprecipitate formed initially was filtered off). The mixture wasconcentrated down, the residue was taken up in ethyl acetate, washedwith 1N hydrochloric acid and water and the organic phase was evaporateddown. The residue was purified by chromatography on silica gel (eluant:ethyl acetate/methylene chloride=1:1).

Yield: 1.4 g (42% of theory),

Melting point: 140°-142° C.

Example XXI

1-[4-(1-Hydroxyimino-ethyl)-phenyl]-3-[4-(2-methoxycarbonylethyl)-phenyl]-imidazolidin-2-one

1.1 g of1-(4-acetyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onewere suspended in a mixture of 10 ml of dioxane and 10 ml of methanol,mixed with a solution of 0.25 g of hydroxylamine-hydrochloride in 4 mlof water and refluxed for 2.5 hours. Then the mixture was evaporateddown in vacuo and the residue was triturated with water, whereupon itcrystallises.

Yield: 1.1 g (92% of theory),

Melting point: 241°-243° C. (sinters from 235° C.)

The following compound was obtained analogously:

(1)1-(1-hydroxyimino-5-indanyl)-3-[4-(2-methoxycarbonylethyl)-phenyl]-imidazolidin-2-one

R_(f) value: 0.13 (silica gel; methylene chloride/ethyl acetate=9:1)

Example XXII

1-(4-Acetyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Prepared analogously to Example 25 from1-[4-(2-methoxycarbonylethyl)-phenyl]-imidazolidin-2-one and4-bromo-acetophenone.

Melting point: 198°-200° C.

R_(f) value: 0.33 (silica gel; methylene chloride/ethyl acetate=25:1)

The following compound was obtained analogously:

(1)1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-(1-oxo-5-indanyl)-imidazolidin-2-one

Melting point: 204°-206° C.

R_(f) value: 0.39 (silica gel; methylene chloride/ethyl acetate=9:1)

Example 1

1-(4'-Amidino-4-biphenylyl)-3-carboxymethyl-imidazolidin-2-one

0.35 g of1-(4'-amidino-4-biphenylyl)-3-methoxycarbonylmethyl-imidazolin-2-onehydrochloride were suspended in 9 ml of methanol. 2.7 ml of 1N sodiumhydroxide solution were added and the mixture was stirred for 16hours atambient temperature. The solvent was distilled off in vacuo and theresidue was mixed with 10 ml of water. Ammonium chloride was added as abuffer. The product precipitated was filtered off.

Yield: 0.19 g (62% of theory),

Melting point: above 200° C.

R_(f) value: 0.61 (Reversed Phase Plate RPS; 10% sodium chloridesolution/methanol=4:6)

Calc.×H₂ O: C 60.65 H 5.67 N 15.72

Found: 61.20 5.57 15.98

The following compounds were obtained analogously:

(1) 1-(4'-amidino-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

Melting point: above 200° C.

R_(f) value: 0.58 (Reversed Phase Plate RP8; 10% sodium chloridesolution/methanol=4:6)

Calc.×0.5 H₂ O: C 63.14 H 5.87 N 15.51

Found: 63.37 5.80 15.13

(2)1-(4'-amidino-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2,4-dione

The starting material used was1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-imidazolidin-2,4-dionehydrochloride

Melting point: above 200° C.

R_(f) value: 0.66 (Reversed Phase Plate RPS; 10% sodium chloridesolution/methanol=4:6)

Calc.×0.25 H20: C 61.52 H 5.01 N 15.11

Found: 61.89 4.97 14.97

(3) 1-(4'-amidino-4-biphenylyl)-3-(2-carboxy-ethyl)-3H-imidazol-2-one

The starting material used was1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-onehydrochloride

Melting point: above 200° C

R_(f) value: 0.68 (Reversed Phase Plate RP8; 5% sodium chloridesolution/methanol=4:6)

Calc.×0.25 H₂ O: C 64.30 H 5.24 N 15.79

Found: 64.61 5.34 15.45

(4)1-(4'-amidino-4-biphenylyl)-3-(2-carboxy-ethyl)-3,4,5,6-tetrahydro-1H-pyrimidin-2-one

The starting material used was1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3,4,5,6-tetrahydro-1H-pyrimidin-2-oneand the work was done in ethanol as solvent

Melting point: above 200° C.

R_(f) value: 0.54 (Reversed Phase Plate RP8; 10% sodium chloridesolution/methanol=4:6)

Calc.×0.25 H20: C 64.76 H 6.12 N 15.11

Found: 64.62 6.13 14.82

(5)1-(4'-amidino-4-biphenylyl)-3-carboxymethyl-3,4,5,6-tetrahydro-1H-pyrimidin-2-one

Melting point: above 200° C.

R_(f) value: 0.63 (Reversed Phase Plate RP8; 10% sodium chloridesolution/methanol=4:6)

Calc.×0.75 H20: C 62.37 H 5.92 N 15.31

Found: 62.39 5.94 15.55

(6)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Lithium hydroxide was used and the solvent was a 5:4 mixture oftetrahydrofuran and water.

Melting point: above 270° C.

R_(f) value: 0.68 (Reversed Phase Plate RP8; 10% sodium chloridesolution/methanol=4:6)

(7)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-3,4,5,6-tetrahydro-1H-pyrimidin-2-one

Lithium hydroxide was used and, as the solvent, a 5:4 mixture oftetrahydrofuran and water was used.

Melting point: above 270° C.

R_(f) value: 0.60 (Reversed Phase Plate RP8; 10% sodium chloridesolution/methanol=4:6)

(8)1-[2-(4'-amidino-4-biphenylyl)-ethyl]-3-carboxymethyl-3H-benzimidazol-2-one

R_(f) value: 0.55 (silica gel; methylene chloride, methanol=6:4)

(9)1-(4'-amidino-3'-fluoro-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(10)1-(4'-amidino-3'-chloro-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(11)1-(4'-amidino-3-methoxy-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(12)1-(4'-amidino-3-bromo-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(13)1-(4'-amidino-3-methylthio-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(14)1-(4'-amidino-3-methylsulphonyl-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(15)1-(4'-amidino-3-methylsulphinyl-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(16)1-(4'-amidino-2,3-dimethyl-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(17)1-(4'-amidino-3-nitro-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(18)1-(4'-amidino-3-amino-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(19)1-(3-acetamino-4'-amidino-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(20)1-(4'-amidino-3-benzoylamino-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(21)2-(4'-amidino-4-biphenylyl)-5-(2-carboxy-ethyl)-3,4-dihydro-2H,5H-1,2,5-thiadiazol-1,1-dioxide

Melting point: above 260° C.

R_(f) value: 0.63 (Reversed Phase Plate RP8; methanol/10% sodiumchloride solution=6:4)

Calc.: C 55.66 H 5.19 N 14.42 S 8.25

Found: 54.42 5.32 14.56 8.26

(22)1-[4-(4-amidino-phenyl)-cyclohexyl]-3-(2-carboxy-ethyl)-3H-imidazol-2-one

(23)1-[4-(4-amidino-phenyl)-cyclohexyl]-3-(2-carboxy-ethyl)-imidazolidin-2-one

(24)1-[1-(4-amidino-phenyl)-4-piperidinyl]-3-(2-carboxy-ethyl)-imidazolidin-2-one

Melting point: above 275° C.

R_(f) value: 0.66 (Reversed Phase Plate RP8; methanol/10% sodiumchloride solution=6:4)

Calc.×0.5 H₂ O: C 58.68 H 7.11 N 19.01

Found: 58.16 7.22 18.76

(25)1-[4-(5-amidino-2-pyridyl)-phenyl]-3-(2-carboxy-ethyl)-imidazolidin-2-one

(26)1-[4-(5-amidino-2-pyrazinyl)-phenyl]-3-(2-carboxy-ethyl)-imidazolidin-2-one

(27)1-[4-(5-amidino-2-pyrimidinyl)-phenyl]-2-(2-carboxy-ethyl)-imidazolidin-2-one

(28)1-[6-(4-amidino-phenyl)-3-pyridazinyl]-3-(2-carboxy-ethyl)-imidazolidin-2-one

Melting point: from 300° C. (decomp.)

R_(f) value: 0.47 (silica gel; butanol/glacial acetic acid/water=4:1:1)

(29)1-[2-(4-amidino-phenyl)-5-pyrimidinyl]-3-(2-carboxy-ethyl)-imidazolidin-2-one

(30)1-[2-(4'-amidino-4-biphenyl)-ethyl]-3-carboxy-methyl-imidazolidin-2-one

(31)1-(4-amidino-3-fluoro-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(32)1-(4-amidino-3-chloro-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(33)1-(4-amidino-2-methylthio-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(34)1-(4-amidino-2-methylsulphinyl-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(35)1-(4-amidino-2-methylsulphonyl-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(36)1-(4-amidino-2-methyl-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Melting point: above 270° C.

R_(f) value: 0.56 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

Calc.: C 65.56 H 6.05 N 15.29

Found: 65.43 6.04 15.36

(37)1-(4-amidino-2-methoxy-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(38)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-2-fluoro-phenyl]-imidazolidin-2-one

(39)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-2-chloro-phenyl]-imidazolidin-2-one

(40)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-2-methoxy-phenyl]-imidazolidin-2-one

(41)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-2-methyl-phenyl]-imidazolidin-2-one

(42)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-2-methylthio-phenyl]-imidazolidin-2-one

(43)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-2-methylsulphinyl-phenyl]-imidazolidin-2-one

(44)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-2-methylsulphonyl-phenyl]-imidazolidin-2-one

(45)1-(4-amidino-phenyl)-3-[5-(2-carboxy-ethyl)-2-pyridyl]-imidazolidin-2-one

(46)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)cyclohexyl]-imidazolidin-2-one

Melting point: above 200° C.

R_(f) value: 0.59 (Reversed Phase Plate RPS; methanol/5% sodium chloridesolution=6:4)

Calc.×0.4 H₂ O: C 62.41 H 7.38 N 15.32

Found: 62.43 7.31 15.18

(47)1-(4-amidino-phenyl)-3-(4-carboxymethyloxy-phenyl)-imidazolidin-2-one

(48)1-(4-amidino-phenyl)-3-(4-carboxymethylthio-phenyl)-imidazolidin-2-one

Melting point: above 275° C.

R_(f) value: 0.56 (Reversed Phase Plate RPS; methanol/10% sodiumchloride solution=6:4)

Calc.×0.5 H₂ O: C 56.98 H 5.05 N 14.76 S 8.45

Found: 56.94 5.15 14.98 8.42

(49)1-(4-amidino-phenyl)-3-(4-carboxymethylsulphinyl-phenyl)-imidazolidin-2-one

Melting point: 252°-254° C. (decomp.)

R_(f) value: 0.79 (Reversed Phase Plate RP8; methanol/10% sodiumchloride solution=6:4)

Calc.×1.5 H₂ O: C 52.28 H 5.12 N 13.55 S 7.74

Found: 52.34 4.97 13.62 8.26

(50)1-(4-amidino-phenyl)-3-(4-carboxymethylsulphonyl-phenyl)-imidazolidin-2-one

Melting point: above 260° C.

R_(f) value: 0.82 (Reversed Phase Plate RP8; methanol/10% sodiumchloride solution=6:4)

Calc.×0.5 H₂ O: C 52.55 H 4.66 N 13.62 S 7.78

Found: 52.88 4.83 13.67 7.99

(51)1-(4-amidino-phenyl)-3-[4-(3-carboxy-2-methyl-2-propyl)-phenyl]-imidazolidin-2-one

Lithium hydroxide was used.

Melting point: above 260° C.

R_(f) value: 0.76 (Reversed Phase Plate RP8; methanol/10% sodiumchloride solution=6:4)

(52)1-(4-amidino-phenyl)-3-[4-(2-carboxy-2-methyl-propyl)-phenyl]-imidazolidin-2-one

(53)1-(4-amino-cyclohexyl)-3-[4-[(2-carboxy-ethyl)-aminocarbonyl]-phenyl]-imidazolidin-2-one

(54)4-(4'-amidino-4-biphenyl)-1-(2-carboxy-ethyl)-3-phenyl-imidazolidin-2-one

(55)1-(4-amidino-phenyl)-3-[2-(4-carboxyphenyl)-ethyl]-imidazolidin-2-one

The work was done with lithium hydroxide and a 2:1 mixture of methanoland dioxane.

Melting point: 320°-325° C. (decomp.)

R_(f) value: 0.55 (Reversed Phase Plate RPS; methanol/5% sodium chloridesolution=6:4)

(56)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethenyl)-phenyl]-imidazolidin-2-one

(57)1-(5-amidino-2-pyridyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(58)1-(1-amidino-4-piperidinyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(59)1-(4-aminomethyl-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Melting point: above 260° C.

R_(f) value: 0.61 (Reversed Phase Plate RPS; methanol/10% sodiumchloride solution=6:4)

Calc.×H₂ O: C 63.85 H 6.49 N 11.76

Found: 64.17 6.50 11.59

(60)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-thione

(61)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-2-imino-imidazolidine

(62)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2,4-dione

Lithium hydroxide was used

Melting point: above 260° C.

R_(f) value: 0.83 (Reversed Phase Plate RPS; methanol/10% sodiumchloride solution=6:4)

Calc.×0.5 H₂ O: C 60.79 H 5.10 N 14.93

Found: 60.69 5.04 15.12

(63)3-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2,4-dione

(64)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-4,4-dimethyl-imidazolidin-2,5-dione

(65)3-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-4,4-dimethyl-imidazolidin-2,5-dione

(66)2-(4-amidino-phenyl)-5-[4-(2-carboxy-ethyl)-phenyl]-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxide

Melting point: above 275° C.

R_(f) value: 0.53 (Reversed Phase Plate RPS; methanol/10% sodiumchloride solution=6:4)

Calc.: C 55.66 H 5.19 N 14.42 S 8.25

Found: 55.84 5.24 14.23 8.01

(67)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-3H-imidazol-2-one

Lithium hydroxide was used.

Melting point: above 260° C.

R_(f) value: 0.58 (Reversed Phase Plate RPS; 10% sodium chloridesolution/methanol=4:6)

(68)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-2-methylimino-imidazolidine

(69)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-2-phenylimino-imidazolidine

(70) 1- (4-amidino-phenyl) -3-[4-(2-carboxy-ethyl)-phenyl ]-2 -(3-pyridylimino)-imidazolidine

(71) 3-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-4-trifluoromethyl-3H-imidazol-2-one

(72) 1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-4-phenyl-3H-imidazol-2-one

(73) 1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-4-phenyl-imidazolidin-2-one

(74)1-[(4-amidino-phenyl)-carbonylmethyl]-3-(3-carboxy-propyl)-imidazolidin-2-one

(75)1-[2-(4-amidino-phenyl)-ethyl]-3-(3-carboxy-propyl)-imidazolidin-2-one

(76)1-[2-(4-amidino-phenyl)-2-hydroxy-ethyl]-3-(3-carboxy-propyl)-imidazolidin-2-one

(77) 1-(4-amidino-phenyl)-3-(4-carboxy-butyl)-imidazolidin-2-one

R_(f) value: 0.50 (silica gel; n-butanol/glacial aceticacid/water=4:1:1)

(78)1-(4-amidino-phenyl)-3-(2-carboxymethylthio-ethyl)-imidazolidin-2-one

(79)1-(4-amidino-phenyl)-3-(2-carboxymethylsulphinyl-ethyl)-imidazolidin-2-one

(80)1-(4-amidino-phenyl)-3-(2-carboxymethylsulphonyl-ethyl)-imidazolidin-2-one

(81)1-(4-amidino-phenyl)-3-(2-carboxymethyloxy-ethyl)-imidazolidin-2-one

(82)1-(4-amidino-phenyl)-3-(2-carboxymethylamino-ethyl)-imidazolidin-2-one

Lithium hydroxide was used.

Melting point: 298° C. (decomp. sintering from 285° C.)

R_(f) value: 0.14 (silica gel; methanol/2N ammonia=5:1, developing threetimes)

(83)1-[2-(N-acetyl-N-carboxymethyl-amino)-ethyl]-3-(4-amidino-phenyl)-imidazolidin-2-one

(84)1-(4-amidino-phenyl)-3-[2-(N-benzoyl-N-carboxymethylamino)-ethyl]-imidazolidin-2-one

(85)1-(4-amidino-phenyl)-3-[1-(2-carboxy-ethyl)-2-oxo-1H-4-pyridyl]-imidazolidin-2-one

(86)1-[4-(2-carboxy-ethyl)-phenyl]-3-(4-ethoxycarbonyl-amidino-phenyl)-imidazolidin-2-one

(87)1-(4-amidino-phenyl)-3-[4-(3-carboxy-propyl)-phenyl]-imidazolidin-2-one

(88)1-(4'-amidino-3-methanesulphonylamino-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(89)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-4H-1,2,4-triazol-5-one

(90)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-4-methyl-4H-1,2,4-triazol-5-one

(91)3-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-4H-1,2,4-triazol-5-one

(92)3-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-4-methyl-4H-1,2,4-triazol-5-one

(93)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl-3H-imidazol-2-one

(94)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-onehydrochloride

Lithium hydroxide was used.

Melting point: 288°-294° C. (decomp.)

(95)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-one

(96)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-3H-imidazol-2-thione

(97)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-3-methyl-3H-imidazol-2-thione

(98)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-thione

(99)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-5-methyl-3H-imidazol-2-one

(100)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-3,5-dimethyl-3H-imidazol-2-one

(101)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-5-methyl-3-phenyl-3H-imidazol-2-one

(102) 4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(103)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-3-methyl-imidazolidin-2-one

(104)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-3-phenyl-imidazolidin-2-one

(105)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-3H-imidazol-2-one

(106)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-3-methyl-3H-imidazol-2-one

(107)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-one

(108)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-3H-imidazol-2-thione

(109)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-3-methyl-3H-imidazol-2-thione

(110)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-thione

(111)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-5-methyl-3-phenyl-3H-imidazol-2-one

(112)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-3,5-dimethyl-3H-imidazol-2-one

(113)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-5-methyl-3H-imidazol-2-one

(114)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(115)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-3-methyl-imidazolidin-2-one

(116)1-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-3-phenyl-imidazolidin-2-one

(117) 4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3H-imidazol-2-onehydrochloride

Melting point: above 280° C.

Calc.×H₂ O: C 56.35 H 5.48 N 13.84 Cl 8.76

Found: 56.56 5.31 13.82 8.96

(118)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-methyl-3H-imidazol-2-onehydrochloride

Melting point: above 280° C.

Calc.×H₂ O: C 57.34 H 5.53 N 13.37 Cl 8.46

Found: 57.37 5.91 13.39 8.79

(119) 4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-phenyl-3H-imidazol-2-onehydrochloride

Melting point: above 280° C.

Calc.×H₂ O: C 62.43 H 5.24 N 11.65 Cl 7.37

Found: 62.66 5.14 11.83 7.67

(120)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3H-imidazol-2-thione

(121)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-methyl-3H-imidazol-2-thione

(122)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-phenyl-3H-imidazol-2-thione

(123)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-5-methyl-3H-imidazol-2-one

(124)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3,5-dimethyl-3H-imidazol-2-one

(125)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-5-methyl-3-phenyl-3H-imidazol-2-one

(126) 4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-imidazolidin-2-one

(127)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-methyl-imidazolidin-2-one

(128)1-[4-(2-carboxy-ethyl)-phenyl]-3-(3-guanidino-phenyl)-imidazolidin-2-one

(129)1-(4-amidino-phenyl)-3-[1-(2-carboxy-ethyl)-4-piperidinyl]-imidazolidin-2-one

(130)1-[4-(2-carboxy-ethyl)-phenyl]-3-(4-methylamidino-phenyl)-imidazolidin-2-one

(131)1-(4-n-butylamidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(132)2-(4-amidino-4'-biphenylyl)-4-(2-carboxy-ethyl)-4H-1,2,4-triazol-3-one

(133)2-(4-amidino-4'-biphenylyl)-4-(2-carboxy-ethyl)-5-methyl-4H-1,2,4-triazol-3-one

(134)4-(4-amidino-4'-biphenylyl)-2-(2-carboxy-ethyl)-4H-1,2,4-triazol-3-one

(135)4-(4-amidino-4'-biphenylyl)-2-(2-carboxy-ethyl)-5-methyl-4H-1,2,4-triazol-3-one

(136)3-(4-amidino-phenyl)-1-(4-carboxy-butyl)-3H-imidazo[4,5-b]pyridin-2-onehydrochloride

R_(f) value: 0.23 (silica gel; methylene chloride/methanol=19:1)

(137)4-(4-amidino-phenyl)-2-[4-(2-carboxy-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

R_(f) value: 0.60 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(138)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-4-methyl-3H-imidazol-2-one

R_(f) value: 0.54 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

Calc.×1.8 H₂ O: C 60.54 H 5.99 N 14.12

Found: 60.95 5.88 14.15

(139)2-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 303°-305° C.

R_(f) value: 0.63 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

Calc.: C 62.45 H 5.24 N 19.17

Found: 62.28 5.28 18.70

(140)2-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-5-ethyl-4H-1,2,4-triazol-3-one

Melting point: above 250° C.

R_(f) value: 0.53 (Reversed Phase Plate RPS; methanol/10% sodiumchloride solution=6:4)

Calc.×1.5 H₂ O: C 59.10 H 5.95 N 17.23

Found: 58.71 6.10 17.03

(141)1-(4-aminomethyl-phenyl)-3-(4-carboxymethyloxy-phenyl)-imidazolidin-2-one

Melting point: above 250° C.

R_(f) value: 0.58 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

Calc.×0.5 H₂ O: C 61.70 H 5.75 N 11.99

Found: 61.48 5.81 12.22

(142)1-(4-aminomethyl-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-3,4,5,6-tetrahydro-1H-pyrimidin-2-one

Melting point: 229°-231° C.

R_(f) value: 0.56 (Reversed Phase Plate RPS; methanol/10% sodiumchloride solution=6:4)

(143)3-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3H-imidazo[4,5-b]pyridin-2-one

R_(f) value: 0.28 (silica gel; methylene chloride/methanol=8:2)

(144)3-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-4-methyl-3H-imidazol-2-one

R_(f) value: 0.54 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(145)2-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

Melting point: 310°-313° C.

R_(f) value: 0.58 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

Calc.: C 59.99 H 5.03 N 19.44

Found: 60.03 5.04 19.15

(146)4-(4-amidino-phenyl)-2-[4-(2-carboxy-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

Melting Point: 313°-316° C.

R_(f) value: 0.61 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

Calc.: C 61.53 H 4.88 N 19.93

Found: 61.42 4.97 20.22

(147)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethenyl)-phenyl]-3H-imidazol-2-one

Melting point: above 350° C.

R_(f) value: 0.45 (Reversed Phase Plate RPS; methanol/10% sodiumchloride solution=6:4)

(148)1-(4-amidino-phenyl)-3-[4-(2-amino-2-carboxy-ethyl)-phenyl]-3H-imidazol-2-one

Lithium hydroxide was used.

R_(f) value: 0.06 (silica gel; methylene chloride/methanol/conc.ammonia=8:4:1)

(149)1-[4-(2-amino-2-carboxy-ethyl)-phenyl]-3-(4-aminomethyl-phenyl)-imidazolidin-2-one

Lithium hydroxide was used.

R_(f) value: 0.15 (silica gel; methylene chloride/methanol/conc.ammonia=16:4:1)

(150)1-(4-amidino-phenyl)-3-[4-(2-carboxy-2-dibenzylamino-ethyl)-phenyl]-3H-imidazol-2-one

Lithium hydroxide was used.

R_(f) value: 0.50 (silica gel; methylene chloride/methanol=4:1)

(151)1-[4-(2-amino-ethyl)-phenyl]-3-(4-carboxymethyl-phenyl)-imidazolidin-2-one

Melting point: above 250° C.

R_(f) value: 0.41 (Reversed Phase Plate RPS; methanol/5% sodium chloridesolution=6:4)

(152)1-[4-(2-amino-2-propyl)-phenyl]-3-[4-(2-carboxyethyl)-phenyl)-imidazolidin-2-one

(153)1-[4-(1-amino-ethyl)-phenyl]-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Melting point: 267°-269° C. (decomp.)

R_(f) value: 0.40 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(154)1-(1-amino-5-indanyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Melting point: 234°-236° C. (decomp.)

(155)1-(1-amino-l,2,3,4-tetrahydro-6-naphthyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(156)1-(4-aminomethyl-2-methyl-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Melting point: 237°-239° C. (decomp.)

R_(f) value: 0.50 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

Calc.×0.8 H₂ O: C 65.31 H 6.74 N 11.42

Found: 65.31 6.68 11.43

(157)1-(4-amidino-phenyl)-3-[4-(2-carboxy-2-dimethylamino-ethyl)-phenyl]-3H-imidazol-2-one

(158)1-(4-amidino-phenyl)-3-[4-(2-carboxy-1-carboxymethyl-ethyl)-phenyl]-imidazolidin-2-one

(159)1-(4-amidino-phenyl)-3-[3,4-bis-carboxymethyloxy-phenyl]-imidazolidin-2-one

(160)3-(4-aminomethyl-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-4-methyl-3H-imidazol-2-one

(161)1-(4-amino-cyclohexyl)-3-[4-(3-carboxy-propyl)-phenyl]-imidazolidin-2-one

(162)1-(4-amino-cyclohexyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(163)1-(4'-aminomethyl-4-biphenylyl)-3-(2-carboxy-ethyl)-imidazolidin-2-one

(164)1-(4-aminomethyl-3-fluoro-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(165)1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-4-methyl-imidazolidin-2-one

(166)1-(4-aminomethyl-phenyl)-3-[3-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(167)1-(4-aminomethyl-phenyl)-3-[4-(2-carboxyl-1-carboxymethyl-ethyl)-phenyl]-imidazolidin-2-one

(168)4-(4-aminomethyl-phenyl)-2-[4-(2-carboxy-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

(169)1-[4-(2-amino-ethyl)-phenyl]-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Half concentrated hydrochloric acid was used at room temperature

Melting point: above 250° C.

R_(f) value: 0.57 (Reversed Phase Plate RP8, glacial aceticacid/water=4:6)

(170)1-[4-(1-amino-2-methyl-2-propyl)-phenyl]-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(171)1-[4-[(2-carboxy-ethyl)-aminocarbonyl]-phenyl]-3-(4-piperidinyl)-imidazolidin-2-one

(172)1-[4-(2-carboxy-ethyl)-phenyl]-3-[4-(dimethylamino-methyl)-phenyl]-imidazolidin-2-one

(173)1-[4-(2-carboxy-ethyl)-phenyl]-3-[4-(methylamino-methyl)-phenyl]-imidazolidin-2-one

(174)1-[4-(2-carboxy-ethyl)-phenyl]-3-[4-(n-propylamino-methyl)-phenyl]-imidazolidin-2-one

(175)2-(4-aminomethyl-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

(176)1-[4-(1-amino-cyclopropyl)-phenyl]-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(177)1-[4-(1-amino-cyclopentyl)-phenyl]-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(178)1-(4-amidino-phenyl)-3-[4-(2-amino-2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Lithium hydroxide was used.

R_(f) value: 0.07 (silica gel; methylene chloride/methanol/conc.ammonia=8:4:1)

(179)1-(4-amidino-phenyl)-3-[4-(2-carboxy-2-hydroxy-ethyl)-phenyl]-3H-imidazol-2-one

(180)1-(4-amidino-phenyl)-3-[4-(2-carboxy-2-methoxy-ethyl)-phenyl]-3H-imidazol-2-one

(181)1-[4-(2-amino-ethyl)-phenyl]-3-(4-carboxymethyloxy-phenyl)-imidazolidin-2-one

The hydrochloride of the ethylester was refluxed in water.

Melting point: above 350° C.

R_(f) value: 0.42 (Reversed Phase Plate RPS; methanol/5% sodium chloridesolution=6:4)

(182)1-[3-(2-amino-ethyl)-phenyl]-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Melting point: above 250° C.

R_(f) value: 0.42 (Reversed Phase Plate RPS; methanol/5% sodiumchloride=6:4)

Calc.×0.3 H₂ O: C 66.95 H 6.63 N 11.71

Found: 66.64 6.65 11.82

(183)1-[4-[(2-carboxy-ethyl)-aminocarbonyl]-phenyl]-3-(1-methyl-4-piperidinyl)-imidazolidin-2-one

(184)1-(4-aminomethyl-cyclohexyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

(185)2-(4-amidino-phenyl)-4-[4-(2-carboxy-2-methyl-propyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

(186)2-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-5-trifluoromethyl-4H-1,2,4-triazol-3-one

(187)2-(4-amidino-phenyl)-4-[4-(2-carboxy-ethyl)-phenyl]-5-phenyl-4H-1,2,4-triazol-3-one

Example 2

1-(4'-Amidino-4-biphenylyl)-3-methoxycarbonylmethyl-imidazolidin-2-onehydrochloride

85 ml of an ice-cooled saturated solution of hydrogen chloride inmethanol were added to 3.1 g of1-(4'-cyano-4-biphenylyl)-3-methoxycarbonylmethyl-imidazolidin-2-one.The resulting suspension was covered with petroleum ether and stirredfor 3.5 hours at ambient temperature. The mixture was evaporated todryness and dried for a further 15 minutes at 1 mbar. The residue wassuspended in 80 ml of absolute methanol, 2.7 g of ammonium carbonatewere added and the resulting mixture was stirred for 16 hours at ambienttemperature. The precipitate was filtered off, the mother liquor wasevaporated down and the residue was purified by column chromatography onsilica gel (eluant: methylene chloride/methanol/conc. ammonia=3:1:0.2).

Yield: 0.7 g (20% of theory),

Melting point: above 200° C.

R_(f) value: 0.53 (silica gel; methylene chloride/methanol/conc.ammonia=3:1:0.2)

The following compounds were obtained analogously:

(1)1-(4'-amidino-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

A four-fold excess of ammonium chloride was used, refluxing for 6 hours.

Melting point: above 200° C.

R_(f) value: 0.40 (silica gel; methylene chloride/methanol/conc.ammonia=5:1:0.2)

(2)1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-imidazolidin-2,4-dionehydrochloride

Ethanolic hydrochloric acid was used in the first phase of the reaction.In the reaction with ammonium carbonate, the mixture was heated to 50°C. for 4 hours. For purification the evaporation residue was stirredwith water.

Melting point: above 200° C.

R_(f) value: 0.50 (silica gel; methylene chloride/methanol=4:1)

Calc.:×HCl×H₂ O: C 56.18 H 5.61 N 12.48 Cl 7.90

Found: 56.41 5.70 12.29 7.78

(3)1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-onehydrochloride

In the first phase of the reaction ethanolic hydrochloric acid was used.In the reaction with ammonium carbonate ethanol was used as solvent.

Melting point: above 200° C.

R_(f) value: 0.27 (silica gel; methylene chloride/methanol conc.ammonia=3:1:0.2)

Calc.×1.2 HCl×H₂ O: C 57.30 H 5.77 N 12.73 Cl 9.66

Found: 57.36 5.83 12.38 9.26

(4)1-(4'-amidino-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3,4,5,6-tetrahydro-1H-pyrimidin-2-onehydrochloride

In the first phase of the reaction ethanolic hydrochloric acid was used.In the reaction with ammonium carbonate the mixture was heated to 50° C.for 4 hours. For purification the evaporation residue was stirred withwater.

Melting point: 212°-215° C.

R_(f) value: 0.47 (silica gel; methylene chloride/methanol conc.ammonia=3:1:0.2)

Calc.×HCl: C 61.32 H 6.32 N 13.00 Cl 8.23

Found: 60.71 6.40 12.85 8.04

(5)1-(4'-amidino-4-biphenylyl)-3-methoxycarbonylmethyl-3,4,5,6-tetrahydro-1H-pyrimidin-2-onehydrochloride

Melting point: above 200° C.

R_(f) value: 0.50 (silica gel; methylene chloride/methanol conc.ammonia=3:1:0.2)

(6)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

Melting point: from 260° C. (decomp.)

The product was also obtained by reacting1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2-onewith methanolic hydrochloric acid.

R_(f) value: 0.49 (Reversed Phase Plate RP8; 10% sodium chloridesolution/methanol=4:6)

(7)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4,5,6-tetrahydro-1H-pyrimidin-2-onehydrochloride

R_(f) value: 0.08 (silica gel; methylene chloride/methanol=95:5)

(8)1-[2-(4'-amidino-4-biphenylyl)-ethyl]-3-methoxycarbonylmethyl-3H-benzimidazol-2-one

R_(f) value: 0.18 (silica gel; methylene chloride/methanol=8:2)

(9)1-(4'-amidino-3'-fluoro-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(10)1-(4'-amidino-3'-chloro-4-biphenylyl)-3-(2-methoxy-carbonyl-ethyl)-imidazolidin-2-onehydrochloride

(11)1-(4'-amidino-3-methoxy-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(12)1-(4'-amidino-3-bromo-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(13)1-(4'-amidino-3-methylthio-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(14)1-(4'-amidino-3-methylsulphonyl-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(15)1-(4'-amidino-2,3-dimethyl-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(16)1-(4'-amidino-3-nitro-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(17)1-(4'-amidino-3-amino-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(18)1-(3-acetamino-4'-amidino-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(19)1-(4'-amidino-3-benzoylamino-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(20)2-(4'-amidino-4-biphenylyl)-5-(2-methoxycarbonyl-ethyl)-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxidehydrochloride

Melting point: 243°-245° C.

R_(f) value: 0.43 (Reversed Phase Plate RPS; methanol/10% sodiumchloride solution=6:4)

(21)1-[4-(4-amidino-phenyl)-cyclohexyl]-3-(2-methoxycarbonyl-ethyl)-3H-imidazol-2-onehydrochloride

(22)1-[4-(4-amidino-phenyl)-cyclohexyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(23)1-[1-(4-amidino-phenyl)-4-piperidinyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(24)1-[4-(5-amidino-2-pyridyl)-phenyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(25)1-[4-(5-amidino-2-pyrazinyl)-phenyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(26)1-[4-(5-amidino-2-pyrimidinyl)-phenyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(27)1-[6-(4-amidino-phenyl)-3-pyridazinyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

Melting point: 303°-305° C. (decomp., sintering from 240° C.)

R_(f) value: 0.42 (silica gel; methylene chloride/methanol/conc.ammonia=8:2:0.1)

(28)1-[2-(4-amidino-phenyl)-5-pyrimidinyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(29)1-[2-(4'-amidino-biphenylyl)-ethyl]-3-methoxycarbonylmethyl-imidazolidin-2-onehydrochloride

(30)1-(4-amidino-3-fluoro-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

(31)1-(4-amidino-3-chloro-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

(32)1-(4-amidino-2-methylthio-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

(33)1-(4-amidino-2-methylsulphonyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

(34)1-(4-amidino-2-methyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

Melting point: 143°-146° C.

R_(f) value: 0.37 (Reversed Phase Plate RPS; methanol/5% sodium chloridesolution=6:4)

(35)1-(4-amidino-2-methoxy-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

(36)1-(4-amidino-phenyl)-3-[2-fluoro-4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

(37)1-(4-amidino-phenyl)-3-[2-chloro-4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

(38)1-(4-amidino-phenyl)-3-[2-methoxy-4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

(39)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-2-methyl-phenyl]-imidazolidin-2-onehydrochloride

(40)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-2-methylthio-phenyl]-imidazolidin-2-onehydrochloride

(41)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-2-methylsulphonyl-phenyl]-imidazolidin-2-onehydrochloride

(42)1-(4-amidino-phenyl)-3-[5-(2-methoxycarbonyl-ethyl)-2-pyridyl]-imidazolidin-2-onehydrochloride

(43)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-cyclohexyl]-imidazolidin-2-onehydrochloride

Melting point: above 200° C.

R_(f) value: 0.44 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(44)1-(4-amidino-phenyl)-3-(4-methoxycarbonyl-methyloxy-phenyl)-imidazolidin-2-onehydrochloride

(45)1-(4-amidino-phenyl)-3-(4-methoxycarbonyl-methylthio-phenyl)-imidazolidin-2-one

Melting point: from 197° C. (decomp.)

R_(f) value: 0.25 (Reversed Phase Plate RP8; methanol/10% sodiumchloride solution=6:4)

(46)1-(4-amidino-phenyl)-3-(4-methoxycarbonyl-methylsulphonyl-phenyl)-imidazolidin-2-onehydrochloride

Melting point: from 249° C. (decomp.)

R_(f) value: 0.43 (Silica gel; methylene chloride/methanol=8:2)

(47)1-(4-amidino-phenyl)-3-[4-(3-methoxycarbonyl-2-methyl-2-propyl)-phenyl]-imidazolidin-2-onehydrochloride

Melting point: 228°-236° C. (decomp.)

R_(f) value: 0.19 (Silica gel; methylene chloride/methanol=9:1)

(48)1-(4-amidino-phenyl)-3-[2-(4-methoxycarbonyl-phenyl)-ethyl]-imidazolidin-2-one

Melting point: 226°-228° C. (decomp.)

R_(f) value: 0.40 (Reversed Phase Plate RPS; methanol/5% sodium chloridesolution=6:4)

(49)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethenyl)-phenyl]-imidazolidin-2-onehydrochloride

(50)1-(5-amidino-2-pridyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

(51)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-thionehydrochloride

(52)1-(4-amidino-phenyl)-2-imino-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidinehydrochloride

(53)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2,4-dionehydrochloride

Melting point: above 260° C.

R_(f) value: 0.19 (silica gel; methylene chloride/methanol=9:1)

Calc.: C 57.62 H 5.08 N 13.44 Cl 8.50

Found: 56.94 5.03 13.33 8.99

(54)3-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2,4-dionehydrochloride

(55)1-(4-amidino-phenyl)-4,4-dimethyl-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2,5-dionehydrochloride

(56)3-(4-amidino-phenyl)-4,4-dimethyl-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2,5-dionehydrochloride

(57)2-(4-amidino-phenyl)-5-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4-dihydro-2H,5H-1,2,5-thiadiazole-l,1-dioxidehydrochloride

Melting point: 245°-248° C. (decomp.)

R_(f) value: 0.44 (Reversed Phase Plate RP8; methanol/10% sodiumchloride solution=6:4)

(58)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onehydrochloride

Melting point: 240° C. (decomp., sintering from 208° C.)

R_(f) value: 0.33 (silica gel; methylene chloride/methanol=5:1)

(59)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-2-methylimino-imidazolidinehydrochloride

(60)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-2-phenylimino-imidazolidinehydrochloride

(61)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-2-(3-pyridyl-imino)-imidazolidinehydrochloride

(62)3-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-trifluoromethyl-3H-imidazol-2-onehydrochloride

(63)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-phenyl-3H-imidazol-2-onehydrochloride

(64)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-phenyl-3H-imidazolidin-2-onehydrochloride

(65)1-[(4-amidino-phenyl)-carbonylmethyl]-3-(3-methoxycarbonyl-propyl)-imidazolidin-2-onehydrochloride

(66)1-[2-(4-amidino-phenyl)-ethyl]-3-(3-methoxycarbonyl-propyl)-imidazolidin-2-onehydrochloride

(67)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-5-onehydrochloride

(68)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-methyl-4H-1,2,4-triazol-5-onehydrochloride

(69)3-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-5-onehydrochloride

(70)3-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-methyl-4H-1,2,4-triazol-5-onehydrochloride

(71) 1-(4-amidino-phenyl)-3-(4-methoxycarbonyl-butyl)-imidazolidin-2-onehydrochloride

R_(f) value: 0.72 (silica gel; methylene chloride/methanol=2:1)

(72)1-(4-amidino-phenyl)-3-(2-methoxycarbonylthio-ethyl)-imidazolidin-2-onehydrochloride

(73)1-(4-amidino-phenyl)-3-(2-methoxycarbonyl-methylsulphonyl-ethyl)-imidazolidin-2-onehydrochloride

(74)1-(4-amidino-phenyl)-3-(2-methoxycarbonyloxy-ethyl)-imidazolidin-2-onehydrochloride

(75)1-(4-amidino-phenyl)-3-(2-methoxycarbonyl-methylamino-ethyl)-imidazolidin-2-onehydrochloride-acetate

Melting point: 197° C. (decomp., sintering from 172° C.)

R_(f) value: 0.44 (silica gel; methylene chloride/methanol/conc.ammonia=8:2:0.1, developing twice)

(76)1-[2-(N-acetyl-N-methoxycarbonylmethyl-amino)-ethyl]-3-(4-amidino-phenyl)-imidazolidin-2-onehydrochloride

(77)1-(4-amidino-phenyl)-3-[2-(N-benzoyl-N-methoxycarbonylmethyl-amino)-ethyl]-imidazolidin-2-onehydrochloride

(78)1-(4-amidino-phenyl)-3-[1-(2-methoxycarbonyl-ethyl)-2-oxo-1H-4-pyridyl]-imidazolidin-2-onehydrochloride

(79)1-(4'-amidino-3-methanesulphonylamino-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

(80)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onehydrochloride

(81)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-3H-imidazol-2-onehydrochloride

Melting point: 242°-246° C. (decomp.)

R_(f) value: 0.50 (silica gel; methylene chloride/methanol=4:1)

(82)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-onehydrochloride

(83)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-thionehydrochloride

(84)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-3H-imidazol-2-thionehydrochloride

(85)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-thionehydrochloride

(86)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-3H-imidazol-2-onehydrochloride

(87)4-(4-amidino-phenyl)-3,5-dimethyl-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onehydrochloride

(88)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-3-phenyl-3H-imidazol-2-onehydrochloride

(89)4-(4'-amidino-4-biphenylyl)-3,5-dimethyl-1-(2-methoxycarbonyl-ethyl)-3H-imidazol-2-onehydrochloride

(90)4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-5-methyl-3-phenyl-3H-imidazol-2-onehydrochloride

(91)4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-5-methyl-3H-imidazol-2-onehydrochloride

(92)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onehydrochloride

(93)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-3H-imidazol-2-onehydrochloride

(94)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-onehydrochloride

(95)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-thionehydrochloride

(96) 1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-3H-imidazol-2 -thione hydrochloride

(97)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-thionehydrochloride

(98)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-3-phenyl-3H-imidazol-2-onehydrochloride

(99)1-(4-amidino-phenyl)-3,5-dimethyl-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onehydrochloride

(100)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-3H-imidazol-2-onehydrochloride

(101)4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3H-imidazol-2-thionehydrochloride

(102)4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-methyl-3H-imidazol-2-thionehydrochloride

(103)4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-3H-imidazol-2-thionehydrochloride

(104)4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3H-imidazol-2-onehydrochloride

Melting point: 278°-282° C. (decomp.)

R_(f) value: 0.30 (silica gel; methylene chloride/methanol=4:1)

(105)4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-methyl-3H-imidazol-2-onehydrochloride

Melting point: 258°-260° C. (decomp.)

R_(f) value: 0.56 (silica gel; methylene chloride/ethanol=4:1)

(106)4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-3H-imidazol-2-onehydrochloride

Melting point: 250°-253° C.

R_(f) value: 0.55 (silica. gel; methylene chloride/ethanol=4:1)

(107)1-(4-amidino-phenyl)-3-[4-(3-methoxycarbonyl-propyl)-phenyl]-imidazolidin-2-onehydrochloride

(108)1-(4-amidino-phenyl)-3-[1-(2-methoxycarbonyl-ethyl)-4-piperidinyl]-imidazolidin-2-onehydrochloride

(109)2-(4-amidino-4'-biphenylyl)-4-(2-methoxycarbonyl-ethyl)-4H-1,2,4-triazol-3-onehydrochloride

(110)2-(4-amidino-4'-biphenylyl)-4-(2-methoxycarbonyl-ethyl)-5-methyl-4H-1,2,4-triazol-3-onehydrochloride

(111)4-(4-amidino-4'-biphenylyl)-2-(2-methoxycarbonyl-ethyl)-4H-1,2,4-triazol-3-onehydrochloride

(112)4-(4-amidino-4'-biphenylyl)-2-(2-methoxycarbonyl-ethyl)-5-methyl-4H-1,2,4-triazol-3-onehydrochloride

(113)1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-(4-methyl-amidino-phenyl)-imidazolidin-2-one

The iminoester was taken up in absolute methanol and reacted with a20-fold excess of a methanolic methylamine solution

(114)1-(4-n-butylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Prepared analogously to (113) with n-butylamine

(115)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-methyl-3H-imidazol-2-onehydrochloride

Melting point: 248° C. (decomp.)

R_(f) value: 0.40 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(116)3-(4-amidino-phenyl)-1-(4-methoxycarbonyl-butyl)-3H-imidazo[4,5-b]pyridin-2-onedihydrochloride

R_(f) value: 0.34 (silica gel; methylene chloride/methanol

(117)4-(4-amidino-phenyl)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-onehydrochloride

Melting point: 273°-275° C.

R_(f) value: 0.55 (silica gel; methylene chloride/methanol=4:1)

(118)2-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-onehydrochloride

Melting point: 272°-274° C.

R_(f) value: 0.37 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(119)2-(4-amidino-phenyl)-5-ethyl-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-onehydrochloride

Melting Point: above 250° C.

R_(f) value: 0.36 (Reversed Phase Plate RPS; methanol/10% sodiumchloride solution=6:4)

Calc.×HCl: C 58.67 H 5.63 N 16.29 Cl 8.25

Found: 58.01 5.65 16.26 9.14

(120)3-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3H-imidazo[4,5-b]pyridin-2-one-hydrochloride

R_(f) value: 0.61 (silica gel; methylene chloride/methanol=8:2)

(121)1-(4-amidino-phenyl)-3-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onehydrochloride

Prepared from1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one,whilst the iminoester formed as an intermediate product was obtained byreacting with ethanolic hydrochloric acid.

R_(f) value: 0.54 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(122)3-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-methyl-3H-imidazol-2-onehydrochloride-hydrate

Melting point: 95°-100° C.

R_(f) value: 0.57 (silica gel; methylene chloride/methanol=4:1)

(123)2-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-onehydrochloride

Melting point: 275°-277° C.

R_(f) value: 0.55 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(124)4-(amidino-phenyl)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-onehydrochloride

Melting point: 289°-291° C. (decomp.)

R_(f) value: 0.49 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(125)1-[1-(4-amidino-phenyl)-4-piperidinyl]-3-(2-methoxycarbonyl-ethyl)-3H-imidazol-2-onehydrochloride

Melting point: above 275° C.

R_(f) value: 0.53 (Reversed Phase Plate RP8; methanol/10% sodiumchloride solution=6:4)

(126)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethenyl)-phenyl]-3H-imidazol-2-onehydrochloride

Melting point: 253°-264° C.

R_(f) value: 0.28 (Reversed Phase Plate RP8; methanol/10% sodiumchloride solution=6:4)

(127)1-(4-amidino-phenyl)-3-[4-(2-dibenzylamino-2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onehydrochloride

R_(f) value: 0.37 (silica gel; methylene chloride/methanol/conc.ammonia=4:1:0.25)

(128)1-(4-amidino-phenyl)-3-[4-(2-amino-2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onedihydrochloride

R_(f) value: 0.18 (silica gel; methylene chloride/methanol/conc.ammonia=16:4:1)

(129)1-(4-amidino-phenyl)-3-[4-(2-dimethylamino-2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

(130)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-1-methoxycarbonylmethyl-ethyl)-phenyl]-imidazolidin-2-one

(131)1-(4-amidino-phenyl)-3-(3,4-bis-methoxycarbonyl-methyloxy-phenyl)-imidazolidin-2-one

(132)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl-phenyl]-4-methyl-imidazolidin-2-one

(133)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-2-methyl-propyl)-phenyl]-imidazolidin-2-one

(134)1-(4-amidino-phenyl)-3-[4-(2-phosphono-ethyl)-phenyl]-imidazolidin-2-one

(135)1-(4-amidino-phenyl)-3-[4-[2-(O-methyl-phosphono)-ethyl]-phenyl]-imidazolidin-2-one

(136)1-(4-amidino-phenyl)-3-[4-[2-(5-tetrazolyl)-ethyl]-phenyl]-imidazolidin-2-one

(137)1-(4-amidino-phenyl)-3-[4-(2-hydroxy-2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

(138)1-(4-amidino-phenyl)-3-[4-(2-methoxy-2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

(139)2-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-2-methyl-propyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

(140)2-(4-amidino-phenyl)-4-[4-(2-phosphono-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

(141)2-(4-amidino-phenyl)-4-[4-[2-(0-methyl-phosphono)-ethyl]-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

(142)2-(4-amidino-phenyl)-4-[4-(2-methyloxycarbonyl-ethyl)-phenyl]-5-trifluoromethyl-4H-1,2,4-triazol-3-one

(143)2-(4-amidino-phenyl)-4-[4-(2-methyloxycarbonyl-ethyl)-phenyl]-5-phenyl-4H-1,2,4-triazol-3-one

(144)2-(4-amidino-phenyl)-4-[4-[2-(5-tetrazolyl)-ethyl]-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

Example 3

1-(4'-Amidino-3-methylsulphinyl-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

Prepared from1-(4'-amidino-3-methylthio-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-oneby oxidation with bromine in glacial acetic acid in the presence ofsodium acetate at ambient temperature.

The following compounds were obtained analogously:

(1)1-(4-amidino-2-methylsulphinyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(2)1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-2-methylsulphinyl-phenyl]-imidazolidin-2-one

(3)1-(4-amidino-phenyl)-3-(2-methoxycarbonylmethyl-sulphinyl-ethyl)-imidazolidin-2-one

Example 4

1-(4-Cyano-phenyl)-3-[2-(4-methoxycarbonyl-phenyl)-ethyl]-imidazolidin-2-one

8.1 g of1-(4-cyano-phenyl)-3-[2-(4-methoxycarbonyl-phenyl)-ethyl]-3H-imidazol-2-onewere dissolved in 750 ml of ethyl acetate and treated with hydrogenunder 5 bar in the presence of 2 g of 10% palladium/charcoal for 2.5hours at 50° C. The catalyst was filtered off, the filtrate wasevaporated down to about 100 ml, 100 ml of tert.butylmethylether wereadded, the resulting mixture was cooled in an ice/acetone bath and theprecipitate formed was filtered off then washed withtert.-butylmethylether.

Yield: 6.4 g (79% of theory),

Melting point: 194°-197° C.

R_(f) value: 0.63 (silica gel; methylene chloride/ethylacetate/cyclohexane=3:1:1)

The following compounds were obtained analogously:

(1)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(2)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-imidazolidin-2-one

(3)4-(4-amidino-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-imidazolidin-2-one

(4)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]imidazolidin-2-one

(5)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-imidazolidin-2-one

(6)1-(4-amidino-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-imidazolidin-2-one

(7)4-(4,-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(8)4-(4,-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-methyl-imidazolidin-2-one

(9)4-(4'-amidino-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-imidazolidin-2-onehydrochloride

The hydrochloride of the free acid was used as starting material and wasreduced in methanol at ambient temperature.

Melting point: 225°-235° C. (decomp.)

(10) 1-[4-(4-amidino-phenyl)-cyclohexyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(11)1-[1-(4-amidino-phenyl)-4-piperidinyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onehydrochloride

Dilute methanolic hydrochloric acid was used and the work was done atambient temperature.

R_(f) value: 0.47 (Reversed Phase Plate; methanol/10% sodium chloridesolution=6:4)

(12)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

Melting point: 160°-162° C.

R_(f) value: 0.59 (silica gel; cyclohexane/ethyl acetate=3:7)

(13)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-phenyl-imidazolidin-2-onehydrochloride

The work was done in ethanol at ambient temperature.

Melting point: 236°-240° C.

(14)4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-3-methyl-imidazolidin-2-onehydrochloride

The work was done in ethanol at ambient temperature.

R_(f) value: 0.55 (Reversed Phase Plate RP18; methanol/5% sodiumchloride solution=6:4)

(15) 4-(4'-amidino-4-biphenylyl)-1-(2-carboxy-ethyl)-imidazolidin-2-onehydrochloride

The work was done in ethanol at ambient temperature.

R_(f) value: 0.61 (Reversed Phase Plate RP18; methanol/5% sodiumchloride solution=6:4)

(16)4-(4-amidino-phenyl)-1-[4-(2-carboxy-ethyl)-phenyl]-3-methyl-imidazolidin-2-onehydrochloride

The work was done in dioxane/water (=1:1).

Melting point: 208°-210° C.

(17)1-(4-amidino-phenyl)-3-[4-(2-amino-2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onedihydrochloride

The work was done in methanol at ambient temperature.

R_(f) value: 0.37 (silica gel; methylene chloride/methanol/conc.ammonia=8:4:1)

(18)1-(4-amidino-phenyl)-3-[4-(2-amino-2-carboxy-ethyl)-phenyl]-imidazolidin-2-one

Melting point: 295° C. (decomp.)

R_(f) value: 0.07 (silica gel; methylene chloride/methanol/conc.ammonia=8:4:1)

Example 5

1-(4-Ethoxycarbonylamidino-phenyl)-3-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

At ambient temperature, 10 ml of 0.2N sodium hydroxide solution wereadded dropwise, with vigorous stirring, to a mixture of 0.3 g of1-(4-amidino-phenyl)-3-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onehydrochloride, 0.07 ml of ethyl chloroformate and 40 ml of methylenechloride. After stirring for 0.5 hours at ambient temperature themethylene chloride phase was separated off and evaporated to dryness.

Yield: 0.29 g (90% of theory),

R_(f) value: 0.48 (silica gel; methylene chloride/methanol=15:1)

Calc.: C 63.99 H 5.82 N 12.44

Found: 64.11 5.98 12.35

The following compounds were obtained analogously:

(1)1-(4-methoxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Melting point: above 260° C.

R_(f) value: 0.73 (silica gel; methylene chloride/methanol=95:5)

(2)1-(4-benzyloxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(3)1-(4-isopropylcarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(4)1-(4-isobutyloxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(5)1-(4-ethoxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(6)4-(4-methoxycarbonylamidino-phenyl)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

Melting point: 296°-298° C.

R_(f) value: 0.46 (silica gel; methylene chloride/methanol=15:1)

(7)4-[4-(2-isopropyloxycarbonyl-ethyl)-phenyl]-2-(4-methoxycarbonylamidino-phenyl)-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 175°-188° C. (decomp.)

R_(f) value: 0.28 (silica gel; methylene chloride/methanol=95:5)

(8)1-(4-methoxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

Melting point: above 260° C.

R_(f) value: 0.27 (silica gel; methylene chloride/methanol=95:5)

Calc.: C 62.55 H 5.25 N 13.26

Found: 62.24 5.33 13.45

(9)1-(4-ethoxycarbonylamidino-phenyl)-3-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Melting point: above 335° C.

R_(f) value: 0.49 (silica gel; methylene chloride/methanol=15:1)

(10)2-(4-methoxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 211°-213° C. (decomp.)

R_(f) value: 0.54 (silica gel; methylene chloride/methanol=15:1)

(11)2-(4-methoxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

Melting point: above 340° C.

R_(f) value: 0.45 (silica gel; methylene chloride/methanol=15:1)

(12)1-(4-methoxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-cyclohexyl]-imidazolidin-2-one

R_(f) value: 0.29 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

(13)1-(4-methoxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2,4-dione

Melting point: 250° C. (decomp., sintering from 198° C.)

R_(f) value: 0.45 (silica gel; ethyl acetate)

Calc.: C 60.27 H 5.06 N 12.78

Found: 60.18 5.12 12.82

(14)1-(4-methoxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-methyl-3H-imidazol-2-one

Melting point: 212°-213° C.

R_(f) value: 0.58 (silica gel; methylene chloride/methanol=9:1)

(15)1-(4-ethoxycarbonylamidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-methyl-3H-imidazol-2-one

Melting point: 198°-199° C.

R_(f) value: 0.58 (silica gel; methylene chloride/methanol=9:1)

(16)2-(4-methoxycarbonylamidino-phenyl)-5-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxide

Melting point: above 275° C.

R_(f) value: 0.23 (silica gel; methylene chloride/methanol=100:3)

(17)2-(4-ethoxycarbonylamidino-phenyl)-5-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxide

Melting point: above 275° C.

R_(f) value: 0.22 (silica gel; methylene chloride/methanol=100:3)

(18)4-[4-(2-isobutyloxycarbonyl-ethyl)-phenyl]-2-(4-methoxycarbonylamidino-phenyl)-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 200°-201° C.

R_(f) value: 0.43 (silica gel; methylene chloride/methanol=95:5)

Calc.: C 62.62 H 6.09 N 14.60

Found: 62.77 6.20 14.88

Example 6

1-(4-Amidino-phenyl)-3-[4-(2-butyloxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

Prepared from1-(4-amidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride by stirring with saturated butanolic hydrochloric acid forthree days at ambient temperature.

The following compound was obtained analogously:

(1)1-(4-amidino-phenyl)-3-[4-[2-(2-phenyl-ethyloxycarbonyl)-ethyl]-phenyl]-imidazolidin-2-onehydrochloride

Example 7

1-(1-Amidino-4-piperidinyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Prepared from1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-(4-piperidinyl)-imidazolidin-2-oneand S-ethylisothiourea-hydrobromide by heating to 100° C. for four hoursin dimethylformamide in the presence of sodium carbonate.

Example 8

1-(4-Aminomethyl-phenyl)-3-(4-methoxycarbonylmethyloxy-phenyl)-imidazolidin-2-onehydrochloride

2 g of1-(4-cyano-phenyl)-3-(4-methoxycarbonylmethyloxy-phenyl)-imidazolidin-2-onewere treated with 5 bars of hydrogen for 2.5 hours at ambienttemperature in a mixture of 40 ml of methanol and 4 ml of methanolichydrochloric acid in the presence of 0.5 g of 10% palladium/charcoal.200 ml of methanol and 50 ml of water were added and the mixture wasfiltered while hot. The product crystallised out upon cooling.

Yield: 1.38 g (62% of theory),

Melting point: above 250° C.

R_(f) value: 0.40 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

Calc.×HCl: C 58.24 H 5.66 N 10.72 Cl 9.05

Found: 58.04 5.65 10.92 9.57

The following compounds were obtained analogously:

(1)1-(4-aminomethyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4,5,6-tetrahydro-1H-pyrimidin-2-onehydrochloride

Melting point: 272°-274° C. (decomp.)

R_(f) value: 0.30 (silica gel; toluene/dioxane/methanol/conc.ammonia=2:5:2:1)

(2)1-(4-aminomethyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

Melting point: above 250° C.

R_(f) value: 0.47 (silica gel; toluene/dioxane/methanol/conc.ammonia=4:10:4:1)

Calc.×HCl: C 61.61 H 6.20 N 10.78 Cl 9.09

Found: 61.30 6.29 10.88 9.12

(3)1-[4-(2-amino-2-methoxycarbonyl-ethyl)-phenyl]-3-(4-aminomethyl-phenyl)-imidazolidin-2-onedihydrochloride

R_(f) value: 0.66 (silica gel; methylene chloride/methanol/conc.ammonia=16:4:1)

(4)1-[4-(2-amino-ethyl)-phenyl]-3-(4-methoxycarbonyl-methyl-phenyl)-imidazolidin-2-one

The work was done at 40° C.

Melting point: above 250° C.

R_(f) value: 0.31 (silica gel; toluene/dioxane/methanol/conc.ammonia=4:10:4:1)

(5)1-(4-aminomethyl-2-methyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Melting point: above 275° C.

R_(f) value: 0.38 (Reversed Phase Plate RPS; methanol/5% sodium chloridesolution=6:4)

(6)3-(4-aminomethyl-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-methyl-3H-imidazol-2-one

(7)1-(4'-aminomethyl-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(8)1-(4-aminomethyl-3-fluoro-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(9)1-(4-aminomethyl-phenyl)-3-[3-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(10)1-(4-aminomethyl-phenyl)-3-[4-(2-methoxycarbonyl-1-methoxycarbonylmethyl-ethyl)-phenyl]-imidazolidin-2-one

(11)4-(4-aminomethyl-phenyl)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

(12)1-[4-(2-amino-ethyl)-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Melting point: above 200° C.

R_(f) value: 0.63 (Reversed Phase Plate RP8; glacial aceticacid/water=1:1)

(13)1-[4-(1-amino-2-methyl-2-propyl)-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(14)2-(4-aminomethyl-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

(15)1-[4-(2-amino-ethyl)-phenyl]-3-(4-methoxycarbonyl-methyloxy-phenyl)-imidazolidin-2-one

(16)1-[3-(2-amino-ethyl)-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one-hydrochloride

The starting1-(3-cyanomethyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-onewas reduced in a mixture of 50 ml of dioxane, 10 ml of methanol and 1 mlof methanolic hydrochloric acid.

Melting point: above 260° C.

R_(f) value: 0.29 (Reversed Phase Plate RPS; methanol/5% sodium chloridesolution=6:4)

(17)1-(4-aminomethyl-cyclohexyl)-3-[4-(2-methyoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Example 9

1-[2-(4-Amidino-phenyl)-2-hydroxy-ethyl]-3-(3-methoxycarbonyl-propyl)-imidazolidin-2-one

Prepared by reduction of1-[(4-amidino-phenyl)-carbonylmethyl]-3-(3-methoxycarbonyl-propyl)-imidazolidin-2-onehydrochloride with sodium borohydride in methanol at 0°-5° C.

Example 10

1-(3-Guanidino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

Prepared from1-(3-amino-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride by refluxing for three hours with cyanamide in dioxane.

Example 11

1-(4'-Cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

2 g of 1-(2-carboxy-ethyl)-3-(4'-cyano-4-biphenylyl)-imidazolidin-2-onewere suspended in 150 ml of methanol, 6 ml of concentrated methanolichydrochloric acid were added and the mixture was stirred for 16 hours atambient temperature. The precipitate was filtered off and purified bycolumn chromatography on silica gel (eluant: methylene chloride/ethylacetate=9:1).

Yield: 0.5 g (23% of theory),

Melting point: 150°-155° C.

R_(f) value: 0.50 (silica gel; methylene chloride/ethyl acetate=9:1)

The following compounds were obtained analogously:

(1)1-(4'-cyano-3'-fluoro-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(2)1-(3'-chloro-4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(3)1-(4'-cyano-3-methoxy-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(4)1-(4'-cyano-3-methylthio-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(5)1-(4'-cyano-2,3-dimethyl-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(6)1-[4-(5-cyano-2-pyridyl)-phenyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(7)1-[4-(5-cyano-2-pyrazinyl)-phenyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(8)1-[4-(5-cyano-2-pyrimidinyl)-phenyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(9)1-[6-(4-cyano-phenyl)-3-pyridazinyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(10)1-[2-(4-cyano-phenyl)-5-pyrimidinyl]-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(11)2-(4-amidino-phenyl)-4-[4-(2-isopropyloxycarbonyl-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-onehydrochloride

Isopropanolic hydrochloric acid was used.

Melting point: 255°-257° C.

R_(f) value: 0.33 (Reversed Phase Plate RPS; methanol/5% sodium chloridesolution=6:4)

(12)2-(4-amidino-phenyl)-4-[4-(2-isobutyloxycarbonyl-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-onehydrochloride

Melting point: above 250° C.

R_(f) value: 0.22 (Reversed Phase Plate RP8; methanol/5% sodium chloridesolution=6:4)

Calc.×HCl: C 60.32 H 6.16 N 15.29 Cl 7.74

Found: 60.19 H 6.28 N 15.37 Cl 7.78

(13)2-(4-amidino-phenyl)-5-ethyl-4-[4-(2-isopropyloxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

Melting point: above 250° C.

R_(f) value: 0.27 (Reversed Phase Plate, RP8; methanol/5% sodiumchloride solution=6:4)

(14)1-(4-amidino-phenyl)-3-[4-(2-isopropyloxycarbonyl-ethyl)-phenyl]-4-methyl-3H-imidazol-2-one

Melting point: 246°-249° C.

R_(f) value: 0.34 (Reversed Phase Plate, RP8; methanol/5% sodiumchloride solution=6:4)

(15)4-(4-amidino-phenyl)-2-[4-(2-isopropyloxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

(16)1-(4-amidino-phenyl)-3-[4[(2-isopropyloxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(17)1-(4-amidino-phenyl)-3-[4-(2-isopropyloxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

Melting point: above 250° C.

R_(f) value: 0.28 (Reversed Phase Plate, RPS; methanol/5% sodiumchloride solution=6:4)

(18)1-(4-amidino-phenyl)-3-[4[(2-isopropyloxycarbonyl-ethyl)-phenyl]-imidazolidin-2,4-dione

Melting point: above 250° C.

R_(f) value: 0.37 (Reversed Phase Plate, RPS; methanol/5% sodiumchloride solution=6:4)

Example 12

1-(2-Carboxy-ethyl)-3-(4'-cyano-4-biphenylyl)-imidazolidin-2-one

3.4 g of 1-(3-buten-1-yl)-3-(4'-cyano-4-biphenylyl)-imidazolidin-2-onewere dissolved in a mixture of 20 ml of methylene chloride and 20 ml ofacetonitrile and 25 mg of ruthenium trichloride trihydrate were added. Amixture of 16 g of sodium metaperiodate and 65 ml of water was added andstirred for 2.5 hours. Then 100 ml of methylene chloride and 20 ml ofwater were added, the phases were separated and the aqueous phase waswashed several times with methylene chloride. The combined organicphases were evaporated down and the powdery residue was used as it waswithout any further purification.

Yield: 2 g (56% of theory),

R_(f) value: 0.12 (silica gel; cyclohexane/ethyl acetate=1:1)

The following compounds were obtained analogously:

(1)1-(2-carboxy-ethyl)-3-(4'-cyano-3,-fluoro-4-biphenylyl)-imidazolidin-2-one

(2)1-(2-carboxy-ethyl)-3-(3'-chloro-4,-cyano-4-biphenylyl)-imidazolidin-2-one

(3)1-(2-carboxy-ethyl)-3-(4'-cyano-3-methoxy-4-biphenylyl)-imidazolidin-2-one

(4)1-(2-carboxy-ethyl)-3-(4'-cyano-3-methylthio-4-biphenylyl)-imidazolidin-2-one

(5)1-(2-carboxy-ethyl)-3-(4'-cyano-2,3-dimethyl-4-biphenylyl)-imidazolidin-2-one

(6)1-(2-carboxy-ethyl)-3-[4-(5-cyano-2-pyridyl)-phenyl]-imidazolidin-2-one

(7)1-(2-carboxy-ethyl)-3-[4-(5-cyano-2-pyrazinyl)-phenyl]-imidazolidin-2-one

(8)1-(2-carboxy-ethyl)-3-[4-(5-cyano-2-pyrimidinyl)-phenyl]-imidazolidin-2-one

(9)1-(2-carboxy-ethyl)-3-[6-(4-cyano-phenyl)-3-pyridazinyl]-imidazolidin-2-one

(10)1-(2-carboxy-ethyl)-3-[2-(4-cyano-phenyl)-5-pyrimidinyl]-imidazolidin-2-one

Example 13

1-(4'-Cyano-4-biphenylyl)-3-methoxycarbonylmethyl-imidazolidin-2-one

4 g of 1-(4'-cyano-4-biphenylyl)-imidazolidin-2-one were dissolved at50° C. in 150 ml of dimethylformamide and 0.73 g of a 95% suspension ofsodium hydride in oil was added in batches thereto. The mixture wasallowed to cool to ambient temperature, then a solution of 1.7 ml ofmethyl bromoacetate in 15 ml of dimethylformamide was added dropwisethereto and the mixture was stirred for 64 hours at ambient temperature.The reaction mixture was poured onto 300 ml of water. The precipitateformed was purified by column chromatography (silica gel; methylenechloride/ethyl acetate=9:1).

Yield: 3.2 g (63% of theory),

R_(f) value: 0.54 (silica gel; cyclohexane/ethyl acetate=1:2)

The following compounds were obtained analogously:

(1)1-(4'-cyano-4-biphenylyl)-3-methoxycarbonylmethyl-3,4,5,6-tetrahydro-1H-pyrimidin-2-one

Melting point: 145°-150° C.

R_(f) value: 0.28 (silica gel; cyclohexane/ethyl acetate=1:2)

(2)1-[2-(4'-cyano-4-biphenylyl)-ethyl]-3-methoxycarbonylmethyl-3H-benzimidazol-2-one

Potassium tert.butoxide was used as base. The4-cyano-4,-(2-iodoethyl)-biphenyl used was obtained from4-(2-bromoethyl)-4'-cyano-biphenyl by reacting with sodium iodide inacetone at ambient temperature.

R_(f) value: 0.89 (silica gel; methylene chloride/methanol=95:5)

(3)1-[2-(4'-cyano-4-biphenylyl)-ethyl]-3-methoxycarbonylmethyl-imidazolidin-2-one

(4)2-(4,-cyano-4-biphenylyl)-5-(2-ethoxycarbonyl-ethyl)-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxide

The work was done in dimethylformamide with potassium tert.butoxide and1-bromo-2-chloro-ethane as alkylating agents.

Melting point: 183°-185° C.

(5) 1-(4-cyano-phenyl)-3-(4-ethoxycarbonyl-butyl)-imidazolidin-2-one

R_(f) value: 0.62 (silica gel; cyclohexane/ethyl acetate=1:3)

(6)3-(4-cyano-phenyl)-1-(4-ethoxycarbonyl-butyl)-3H-imidazo[4,5-b]pyridin-2-one

R_(f) value: 0.78 (silica gel; methylene chloride/methanol=9:1)

Example 14

1-(4,-Cyano-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3,4,5,6-tetrahydro-1H-pyrimidin-2-one

1.9 g ofN-(4'-cyano-4-biphenylyl)-N-(3-methane-sulphonyloxy-propyl)-N'-(2-ethoxycarbonyl-ethyl)-ureawere dissolved in 2 ml of dimethylformamide, 0.18 g of a 55% suspensionof sodium hydride in oil was added thereto at ambient temperature andthe mixture was stirred at ambient temperature for 2 hours. 20 ml ofwater were added and the precipitate formed was purified by columnchromatography (silica gel; ethyl acetate).

Yield: 1.0 g (64% of theory),

Melting point: 137°-138° C.

R_(f) value: 0.57 (silica gel; cyclohexane/ethyl acetate=1:5)

The following compounds were obtained analogously:

(1)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Melting point: 160°-162.5° C.

R_(f) value: 0.59 (silica gel; cyclohexane/ethyl acetate=3:7)

(2)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4,5,6-tetrahydro-1H-pyrimidin-2-one

Melting point: 149°-152° C.

R_(f) value: 0.25 (silica gel; cyclohexane/ethyl acetate=1:1)

(3)1-(4-cyano-3-fluoro-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(4)1-(3-chloro-4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(5)1-(4-cyano-2-methylthio-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(6)1-(4-cyano-2-methyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(7)1-(4-cyano-2-methoxy-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(8)1-(4-cyano-phenyl)-3-[2-fluoro-4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(9)1-[2-chloro-4-(2-methoxycarbonyl-ethyl)-phenyl]-3-(4-cyano-phenyl)-imidazolidin-2-one

(10)1-(4-cyano-phenyl)-3-[2-methoxy-4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(11)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-2-methyl-phenyl]-imidazolidin-2-one

(12)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-2-methylthio-phenyl]-imidazolidin-2-one

(13)1-(4-cyano-phenyl)-3-[5-(2-methoxycarbonyl-ethyl)-2-pyridyl]-imidazolidin-2-one

(14)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-cyclohexyl]-imidazolidin-2-one

(15)1-(4-cyano-phenyl)-3-(4-methoxycarbonylmethyloxy-phenyl)-imidazolidin-2-one

(16)1-(4-tert.butyloxycarbonylmethylthio-phenyl)-3-(4-cyano-phenyl)-imidazolidin-2-one

Melting point: 169°-171° C.

(17)1-(4-cyano-phenyl)-3-[4-(3-methoxycarbonyl-2-methyl-2-propyl)-phenyl]-imidazolidin-2-one

Sodium iodide was added and potassium tert.butoxide was used as base.

Melting point: 177°-179° C.

(18)1-(4-cyano-phenyl)-3-[2-(4-ethoxycarbonyl-phenyl)-ethyl]-imidazolidin-2-one

(19)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethenyl)-phenyl]-imidazolidin-2-one

(20)1-(5-cyano-2-pyridyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(21)1-(4-cyano-phenyl)-3-[4-(3-methoxycarbonyl-propyl)-phenyl]-imidazolidin-2-one

(22)1-(4-cyanomethyl-phenyl)-3-(4-methoxycarbonyl-methyl)-phenyl]-imidazolidin-2-one

The iodide [R_(f) value: 0.66 (silica gel; cyclohexane/ethylacetate=3:7)] obtained from the corresponding mesylate was used.

Melting point: 157°-160° C.

R_(f) value: 0.30 (silica gel; cyclohexane/ethyl acetate=4:6)

Example 15

1-(4'-Cyano-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-one

A mixture of 2.8 g ofN-(4'-cyano-4-biphenylyl)-N-(2,2-diethoxy-ethyl)-N'-(2-ethoxycarbonyl-ethyl)-urea,2.8 ml of 2N hydrochloric acid and 28 ml of ethanol was refluxed for 45minutes. The reaction mixture was cooled to 0° C., the productprecipitated was suction filtered and washed with ethanol at 0° C.

Yield: 1.4 g (63% of theory),

Melting point: 140°-142° C.

R_(f) value: 0.40 (silica gel; cyclohexane/ethyl acetate=1:1)

The following compounds were obtained analogously:

(1)1-[4-(4-cyano-phenyl)-cyclohexyl]-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-one

(2)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

The work was done with methanolic hydrochloric acid.

Melting point: 153°-155° C.

(3)1-(4-cyano-phenyl)-3-[2-(4-methoxycarbonyl-phenyl)-ethyl]-3H-imidazol-2-one

Melting point: 181°-183° C.

(4)1-[1-(4-cyano-phenyl)-4-piperidinyl]-3-(2-ethoxycarbonyl-ethyl)-3H-imidazol-2-one

Melting point: 153°-155° C.

(5)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethenyl)-phenyl]-3H-imidazol-2-one

Melting point: 210°-212° C.

R_(f) value: 0.76 (silica gel; methylene chloride/ethyl acetate=9:1)

(6)1-(4-cyano-phenyl)-3-[4-(2-dibenzylamino-2-methoxy-carbonyl-ethyl)-phenyl]-3H-imidazol-2-one

R_(f) value: 0.40 (silica gel; cyclohexane/ethyl acetate=2:1)

(7)1-[4-(2-amino-2-methoxycarbonyl-ethyl)-phenyl]-3-(4-cyano-phenyl)-3H-imidazol-2-onehydrochloride

R_(f) value: 0.82 (silica gel; methylene chloride/methanol/conc.ammonia=16:4:1)

Example 16

1-(4'-Cyano-4-biphenylyl)-3-(2-ethoxycarbonyl-ethyl)-imidazolidin-2,4-dione

5 g ofN-(tert.butyloxycarbonyl-methyl)-N-(4'-cyano-4-biphenylyl)-N'-(2-ethoxycarbonyl-ethyl)-ureawere dissolved in 30 ml of methylene chloride, 30 ml of trifluoroaceticacid were added and the resulting mixture was stirred at ambienttemperature for 16 hours. It was evaporated to dryness, digested withwater and the precipitate was recrystallised fromtert.butyl-methylether/ethyl acetate=1:1.3.

Yield: 2.9 g (55% of theory),

Melting point: 177°-178° C.

R_(f) value: 0.57 (silica gel; methylene chloride/ethyl acetate=7:1)

The following compound was obtained analogously:

(1)1-(4-aminomethyl-phenyl)-3-[4-[2-(5-tetrazolyl)-ethyl]-phenyl]-imidazolidin-2-one

Example 17

1-(3-Bromo-4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

Prepared by reacting1-(4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onewith bromine in glacial acetic acid at ambient temperature.

Example 18

1-(4-Amidino-phenyl)-3-(methoxycarbonylmethylsulphonyl-phenyl)-imidazolidin-2-one

2.1 g of1-(4-amidino-phenyl)-3-(methoxycarbonylmethyl-thio-phenyl)-imidazolidin-2-onewere suspended in 10 ml of formic acid, 1.3 ml of 30% hydrogen peroxidewere added and the mixture was stirred at ambient temperature for 16hours. The precipitate formed was filtered off (see Example (2)), excessperoxide was destroyed by the addition of sodium bisulphite solution andthe remainder was evaporated down in vacuo. The residue was extracted byboiling with a mixture of 100 ml of methylene chloride and 60 ml ofmethanol. The solution obtained was evaporated down and the residue waspurified by column chromatography (silica gel; methylenechloride/methanol=9:1). In addition to 1 mol of water the productcontains 0.5 mol of hydrochloric acid and 1 mol of formic acid.

Yield: 0.25 g (10% of theory)

R_(f) value: 0.43 (silica gel; methylene chloride/methanol=8:2)

The following compounds were obtained analogously:

(1)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-2-methylsulphonyl-phenyl]-imidazolidin-2-one

(2)1-(4-cyano-phenyl)-3-(4-methoxycarbonylmethyl-sulphonyl-phenyl)-imidazolidin-2-one

(Obtained as a by-product of Example 18)

Melting point: 246°-249° C.

(3)1-(4-cyano-2-methylsulphonyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(4)1-(4'-cyano-3-methylsulphonyl-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(5)1-(4-amidino-phenyl)-3-(4-methoxycarbonylmethyl-sulphinyl-phenyl)-imidazolidin-2-one

The work was done in glacial acetic acid at 10° C. with equimolaramounts of hydrogen peroxide.

Melting point: from 215° C. (decomp.)

R_(f) value: 0.48 (Reversed Phase Plate RP8, methanol/10% sodiumchloride solution=6:4)

Example 19

1-(4'-Cyano-3-nitro-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

Prepared by reacting1-(4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onewith fuming nitric acid at 0° C.

Example 20

1-(3-Amino-4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

Prepared by reduction of1-(4'-cyano-3-nitro-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-onewith hydrogen at 5 bars in the presence of 5% palladium/charcoal inethyl acetate at ambient temperature.

Example 21

1-(3-Acetamino-4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

Prepared from1-(3-amino-4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-oneand acetylchloride in methylene chloride at ambient temperature usingethyl-diisopropylamine.

The following compounds were obtained analogously:

(1)1-(3-benzoylamino-4'-cyano-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

(2)1-(4'-cyano-3-methanesulphonylamino-4-biphenylyl)-3-(2-methoxycarbonyl-ethyl)-imidazolidin-2-one

Example 22

1-(4-Cyano-phenyl)-3-[4-(2-phosphono-ethyl)-phenyl]-imidazolidin-2-one

Prepared from a mixture of1-(4-cyano-phenyl)-3-[4-[2-(dimethoxy-phosphoryl)-ethyl]-phenyl]-imidazolidin-2-one,sodium iodide and trimethylchlorosilane in acetonitrile by stirring at40° C.

The following compound was obtained analogously:

(1)1-(4-cyano-phenyl)-3-[4-[2-(O-methyl-phosphono)-ethyl]-phenyl]-imidazolidin-2-one

Sodium iodide was used on its own and the work was done by refluxing inmethylethylketone.

Example 23

1-(4-Cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-thione

Prepared by heating1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onewith2,4-bis-(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetan-2,4-disulphide inxylene.

The following compounds were obtained analogously:

(1)4-(4-cyano-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-thione

(2)1-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-thione

Example 24

4-(4'-Cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-methyl-3H-imidazol-2-one

A mixture of 8.4 g of4-cyano-4'-[(2-methoxycarbonyl-ethyl)-aminomethyl-carbonyl]-biphenylhydrochloride, 2.8 ml of methylisocyanate and 50 ml of pyridine wasrefluxed for 3 hours and then stirred into a mixture of ice andhydrochloric acid. It was extracted with ethyl acetate, the organicphase was concentrated by evaporation and the residue was triturated,until it crystallised, with a 1:1 mixture of ethyl acetate and ether.

Yield: 2.1 g (35% of theory),

Melting point: 128°-130° C.

The following compounds were obtained analogously:

(1)4-(4-cyano-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

Trimethylsilylisocyanate was used.

(2)4-(4-cyano-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-one

(3)4-(4-cyano-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-3H-imidazol-2-thione

Methylisothiocyanate was used.

(4)4-(4-cyano-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-thione

Phenylisothiocyanate was used.

(5)4-(4-cyano-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-3H-imidazol-2-one

(6)4-(4-cyano-phenyl)-3,5-dimethyl-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

(7)4-(4-cyano-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-3-phenyl-3H-imidazol-2-one

(8)1-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

(9)1-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-3H-imidazol-2-one

(10)1-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-one

(11)1-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-3H-imidazol-2-thione

(12)1-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-phenyl-3H-imidazol-2-thione

(13)1-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-3-phenyl-3H-imidazol-2-one

(14)1-(4-cyano-phenyl)-3,5-dimethyl-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3H-imidazol-2-one

(15)1-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-3H-imidazol-2-one

(16)4-(4,-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3H-imidazol-2-one

Potassium isocyanate and water were used as solvents.

Melting point: 235°-240° C.

(17)4-(4-cyano-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-methyl-3H-imidazol-2-one

Prepared from the methyl 4-[(4-cyano-phenacyl)-amino]-cinnamate preparedin situ according to Example IV without the addition of auxiliary base.

Melting point: 140°-144° C.

(18)4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-3H-imidazol-2-one

Melting point: 103°-107° C.

(19)4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3H-imidazol-2-thione

(20) 4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-methyl-3H-imidazol-2-thione

(21) 4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3-phenyl-3H-imidazol-2-thione

(22)4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-5-methyl-3H-imidazol-2-one

(23)4-(4'-cyano-4-biphenylyl)-3,5-dimethyl-1-(2-methoxycarbonyl-ethyl)-3H-imidazol-2-one

(24)4-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-5-methyl-3-phenyl-3H-imidazol-2-one

Example 25

1-(4-Cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-cyclohexyl]-imidazolidin-2-one

A mixture of 2.25 g of1-[4-(2-methoxycarbonyl-ethyl)-cyclohexyl]-imidazolidin-2-one, 2.25 g of4-iodo-benzonitrile, 0.29 g of tris-[2-(2-methoxy-ethoxy)-ethyl]-amine,2.46 g of potassium carbonate, 0.2 g of copper(I)chloride, 0.2 g ofcopper(I)iodide and 60 ml of xylene was heated under nitrogen for 4hours using a water separator. The mixture was allowed to cool to 50°C., 150 ml of ethyl acetate were added, the precipitate was filtered offwhile hot and washed with hot ethyl acetate. The ethyl acetate phaseswere evaporated to dryness and the residue was purified by columnchromatography over silica gel (eluant: cyclohexane/ethyl acetate=1:1).

Yield: 1.7 g (54% of theory),

R_(f) value: 0.56 (silica gel; cyclohexane/ethyl acetate=1:1)

The following compound was obtained analogously:

(1)2-64=cyano-phenyl)-5-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxide4-Fluoro-benzonitrile and sodium hydride in N-methyl-pyrrolidone wereused without copper salts.

Melting point: 160°-162° C.

Example 26

3-(4-Cyano-phenyl)-1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-methyl-3H-imidazol-2-one

3 g ofN-(4-cyano-phenyl)-N'-(2-hydroxy-propyl)-N'-[4-(2-methoxycarbonyl-ethyl)-phenyl]-ureawere dissolved in a mixture of 40 ml of methylene chloride and 20 ml ofdimethylsulphoxide and 0.64 ml of pyridine, 0.61 ml of trifluoroaceticacid and 4.9 g of N,N'-dicyclohexyl-carbodiimide were addedsuccessively. The mixture was stirred for 4.5 hours at ambienttemperature, a further 5 ml of trifluoroacetic acid were added and themixture was heated for one hour to 50° C. It was left to stand for 16hours at ambient temperature, diluted with 150 ml of methylene chlorideand washed several times with water. The methylene chloride phase wasevaporated down and the residue was purified by column chromatographyover silica gel (eluant: methylene chloride/cyclohexane/ethylacetate=2:1:1).

Yield: 0.8 g (28% of theory),

R_(f) value: 0.55 (silica gel; methylene chloride/cyclohexane/ethylacetate=3:1:1)

The following compound was obtained analogously:

(1)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4-methyl-3H-imidazol-2-one

Melting point: 168°-170° C.

R_(f) value: 0.55 (silica gel; methylene chloride/cyclohexane/ethylacetate=2:1:1)

Example 27

4-(4-Cyano-phenyl)-2-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

1.75 g ofN-acetylamino-N-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-N'-(4-cyano-phenyl)-ureawere heated to 180° C. for 1.5 hours. The compound was triturated with 8ml of ethanol and the resulting product was filtered off.

Yield: 0.66 g (40% of theory),

Melting point: 170°-172° C.

R_(f) value: 0.91 (silica gel; ethyl acetate/cyclohexane=2:1)

The following compounds were obtained analogously:

(1)4-(4-cyano-phenyl)-2-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

Melting point: 213°-215° C.

R_(f) value: 0.69 (silica gel; methylene chloride/ethyl acetate=9:1)

(2)2-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-4H-1,2,4-triazol-3-one

R_(f) value: 0.62 (silica gel; methylene chloride/ethyl acetate=9:1)

(3)2-(4-cyano-phenyl)-4-[4-(2-methoxycarbonyl-ethyl)-phenyl]-5-methyl-4H-1,2,4-triazol-3-one

Melting point: 163°-164° C.

R_(f) value: 0.65 (silica gel; methylene chloride/ethyl acetate=9:1)

(4)1-(4-cyano-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2,4-dione

Melting point: 188°-190° C.

R_(f) value: 0.57 (silica gel; cyclohexane/ethyl acetate=4:6)

(5)2-(4-cyano-phenyl)-4-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-5-ethyl-4H-1,2,4-triazol-4-one

The starting compound was refluxed in xylene in the presence oftoluenesulphonic acid.

Melting point: 159°-161° C.

R_(f) value: 0.68 (silica gel; methylene chloride/ethyl acetate=9:1)

Example 28

1-[6-(4-Cyano-phenyl)-3-pyridazinyl]-3-(2-methoxy-carbonyl-ethyl)-imidazolidin-2-one

2.2 g of 1-[6-(4-cyano-phenyl)-3-pyridazinyl]-imidazolidin-2-one werestirred into 160 ml of dimethylformamide with 0.33 g of a 60% suspensionof sodium hydride in oil for 3 hours at ambient temperature. 2 ml ofmethyl acrylate were added and the mixture was stirred for a further 16hours at ambient temperature. The reaction mixture was poured onto amixture of 300 ml of water and 8 ml of 1N hydrochloric acid, the productprecipitated was filtered off, brought to the boil with methanol and,after cooling, filtered again.

Yield: 1.8 g (60% of theory),

R_(f) value: 0.46 (silica gel; methylene chloride/methanol=15:1,developing twice)

The following compound was obtained analogously:

(1)3-(4'-cyano-4-biphenylyl)-1-(2-methoxycarbonyl-ethyl)-3H-imidazo[4,5-b]pyridin-2-one

R_(f) value: 0.81 (silica gel; methylene chloride/methanol=19:1)

Example 29

1-(2-tert.Butoxycarbonylmethylamino-ethyl)-3-(4-cyano-phenyl)-imidazolidin-2-one

A solution of 4.6 g of1-(4-cyano-phenyl)-3-(2-methanesulphonyloxy-ethyl)-imidazolidin-2-one in75 ml of dimethylformamide was mixed with 2.1 g of potassium carbonateat ambient temperature, with stirring, and then 2.1 ml ofglycine-tert.butylester were added dropwise. The resulting mixture wasstirred for 16 hours at ambient temperature and 30 hours at 60° C. Thesolvent was distilled off in vacuo and the residue was taken up in amixture of 150 ml of ice water and 100 ml of methylene chloride. Themethylene chloride phase was separated off and washed with water. Theaqueous phases were then extracted once more with methylene chloride andfinally the combined organic phases were evaporated down. The residuewas purified over silica gel (eluant: ethyl acetate/methanol/conc.ammonia=9.5:0.5:0.1).

Yield: 1.4 g (27% of theory),

Melting point: 104°-106° C.

R_(f) value: 0.32 (silica gel; ethyl acetate/methanol/conc.ammonia=9:1:0.1)

Example 30

1- [2 - (N-Acetyl-N-carboxymethyl-amino) -ethyl ]- 3 - (4-amidino-phenyl)-imidazolidin-2- one

A mixture of 0.3 g of1-(4-amidino-phenyl)-3-(2-carboxymethylamino-ethyl)-imidazolidin-2-oneprepared under ice cooling, 20 ml of water and 2.35 ml of acetanhydridewas allowed to return to ambient temperature with stirring and stirredfor a further 30 minutes. It was then evaporated to dryness in vacuo andthe residue was purified by chromatography on silica gel (eluant:methanol/glacial acetic acid/water=6:1:1)

Yield: 0.2 g (57% of theory),

Melting point: 302°-304° C. (decomp.)

R_(f) value: 0.54 (silica gel; methanol/2N aqueous ammonia=4:1)

Example 31

1-[4-(1-Amino-ethyl)-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

0.5 g of1-[4-(1-hydroxyimino-ethyl)-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onewere treated with hydrogen at 5 bars for 3.5 hours at ambienttemperature in a mixture of 50 ml of methanol and 1 ml of methanolichydrochloric acid in the presence of 100 mg of 10% palladium/charcoal.The mixture was evaporated down and the residue was taken up in amixture of 20 ml of methylene chloride, 15 ml of methanol, 20 ml ofwater and 0.1 ml of 6N hydrochloric acid. The aqueous phase wasseparated off and evaporated down to about one third of its volume,whereupon the product crystallised out.

Yield: 0.28 g (53% of theory),

Melting point: 264°-266° C.

R_(f) value: 0.51 (Reversed Phase Plate RP8, methanol/5% sodium chloridesolution=6:4)

The following compounds were obtained analogously:

(1)1-(1-amino-5-indanyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

Melting point: 223°-226° C. (sintering from 208° C.)

(2)1-(1-amino-1,2,3,4-tetrahydro-6-naphthyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-onehydrochloride

Example 32

1-(4-Amino-cyclohexyl)-3-[4-(3-methoxycarbonyl-propyl)-phenyl]-imidazolidin-2-one

Prepared from1-(4-aminocarbonyl-cyclohexyl)-3-[4-(3-methoxycarbonyl-propyl)-phenyl]-imidazolidin-2-oneby treating with [bis-(trifluoroacetoxy) iodo]benzene inacetonitrile/water at ambient temperature.

The following compounds were obtained analogously:

(1)1-(4-amino-cyclohexyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

(2)1-[4-(2-amino-2-propyl)-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Example 33

1-[4-[(2-Methoxycarbonyl-ethyl)-aminocarbonyl]-phenyl]-3-(4-piperidinyl)-imidazolidin-2-one

Prepared by treating1-(1-benzyloxycarbonyl-4-piperidinyl)-3-[4-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-phenyl]-imidazolidin-2-onewith hydrogen at 3 bars in the presence of 5% palladium/charcoal inmethanol.

The following compounds were obtained analogously:

(1)1-(4-amino-cyclohexyl)-3-[4-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-phenyl]-imidazolidin-2-one

(2)1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-[4-(methylaminomethyl)-phenyl]-imidazolidin-2-one

(3)1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-[4-(n-propylamino-methyl)-phenyl]-imidazolidin-2-one

Example 34

1-[4-(1-Amino-cyclopropyl)-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Prepared from1-[4-(1-tert.butyloxycarbonylamino-cyclopropyl)-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-oneby stirring for two hours in a 1:1 mixture of methylene chloride andtrifluoroacetic acid.

The following compound was obtained analogously:

(1)1-[4-(1-amino-cyclopentyl)-phenyl]-3-[4-[(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Example 35

1-[4-(2-Methoxycarbonyl-ethyl)-phenyl]-3-[4-(methylamino-methyl)-phenyl]-imidazolidin-2-one

Prepared from1-(4-aminomethyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-oneby alkylation with methyliodide in dimethylsulphoxide.

The following compounds were obtained analogously:

(1)1-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3-[4-(n-propylamino-methyl)-phenyl]-imidazolidin-2-one

(2)1-[4-(2-methoxycarbonyl-ethyl)-aminocarbonyl]-phenyl]-3-(1-methyl-4-piperidinyl)-imidazolidin-2-one

Example 36

1-(4-Cyano-2-methyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

3.0 g of1-(4-bromo-2-methyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-oneand 1.3 g of copper(I)cyanide were heated in 10 ml of dimethylformamidefor 10 hours at a bath temperature of 175° C. The dimethylformamide wasevaporated off in vacuo, the residue was digested with chloroform andfiltered off. The chloroform solution was washed with water andsaturated saline solution and concentrated by evaporation. The residuewas purified by column chromatography (silica gel; methylenechloride/ethyl acetate=100:2)

Yield: 1.4 g (54% of theory),

Melting point: 151°-153° C.

Example 37

1-[4-(Dimethylamino-methyl)-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one

Prepared from1-(4-aminomethyl-phenyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-oneby treating with formaldehyde and sodium cyanoborohydride.

Example 38

Dry ampoule containing 2.5 mg of active substance per 1 ml

    ______________________________________                                        Composition:                                                                  ______________________________________                                        Active substance 2.5          mg                                              Mannitol         50.0         mg                                              Water for injections ad                                                                        1.0          ml                                              ______________________________________                                    

Preparation:

The active substance and mannitol were dissolved in water. Afterpackaging, the ampoules were freeze-dried.

The solution ready for use was made up with water for injections.

Example 39

Dry ampoule containing 35 mg of active substance per 2 ml

    ______________________________________                                        Composition:                                                                  ______________________________________                                        Active substance 35.0         mg                                              Mannitol         100.0        mg                                              Water for injections ad                                                                        2.0          ml                                              ______________________________________                                    

Preparation:

The active substance and mannitol were dissolved in water. Afterpackaging, the ampoules were freeze-dried.

The solution ready for use was made up with water for injections.

Example 40

Tablet containing 50 mg of active substance

    ______________________________________                                        Composition:                                                                  ______________________________________                                        (1) Active substance    50.0 mg                                               (2) Lactose             98.0 mg                                               (3) Corn starch         50.0 mg                                               (4) Polyvinylpyrrolidone                                                                              15.0 mg                                               (5) Magnesium stearate  2.0 mg                                                                       215.0 mg                                               ______________________________________                                    

Preparation:

(1), (2) and (3) were mixed together and granulated with an aqueoussolution of (4). (5) was added to the dried granules. From this mixture,compressed tablets were made, which were biplanar, facetted on bothsides and notched on one side. Diameter of tablets: 9 mm.

Example 41

Tablet containing 350 mg of active substance

    ______________________________________                                        Composition:                                                                  ______________________________________                                        (1) Active substance   350.0 mg                                               (2) Lactose            136.0 mg                                               (3) Corn starch         80.0 mg                                               (4) Polyvinylpyrrolidone                                                                              30.0 mg                                               (5) Magnesium stearate  4.0 mg                                                                       600.0 mg                                               ______________________________________                                    

Preparation:

(1), (2) and (3) were mixed together and granulated with an aqueoussolution of (4). (5) was added to the dried granules. From this mixture,compressed tablets were made, which were biplanar, facetted on bothsides and notched on one side. Diameter of tablets: 12 mm.

Example 42

Capsules containing 50 mg of active substance

    ______________________________________                                        Composition:                                                                  ______________________________________                                        (1) Active substance    50.0 mg                                               (2) Dried corn starch   58.0 mg                                               (3) Powdered lactose    50.0 mg                                               (4) Magnesium stearate  2.0 mg                                                                       160.0 mg                                               ______________________________________                                    

Preparation:

(1) was triturated with (3). This trituration was added to the mixtureof (2) and (4) with thorough mixing.

The powdered mixture was packed into hard gelatin oblong capsules, size3, in a capsule filling machine.

Example 43

Capsule containing 350 mg of active substance

    ______________________________________                                        Composition:                                                                  ______________________________________                                        (1) Active substance   350.0 mg                                               (2) Dried corn starch   46.0 mg                                               (3) Powdered lactose    30.0 mg                                               (4) Magnesium stearate  4.0 mg                                                                       430.0 mg                                               ______________________________________                                    

Preparation:

(1) was triturated with (3). This trituration was added to the mixtureof (2) and (4) with thorough mixing.

The powdered mixture was packed into hard gelatin oblong capsules, size0, in a capsule filling machine.

What is claimed is:
 1. An imidazolidindione of formula ##STR24## whereinY represents a --CR_(c) R_(d) CO-- group, whereinR_(c) represents ahydrogen atom, an C₁₋₃ -alkyl, trifluoromethyl or phenyl group, andR_(d) represents a hydrogen atom or an C₁₋₃ -alkyl group; one of thegroups R_(a) or R_(b) represents a group of formula

    A-B-C-

wherein A represents a straight-chained or branched C₁₋₄ -aminoalkylgroup, an amino, amidino or guanidino group, wherein in each of theabove-mentioned groups, at one of the nitrogen atoms, one hydrogen atommay be replaced by a C₁₋₄ -alkyl group or an alkoxycarbonyl group havinga total of 2 to 5 carbon atoms or by a benzyloxycarbonyl group, Brepresents a bond, a phenylene group which may be substituted by one ortwo C₁₋₄ -alkyl groups, by a fluorine, chlorine, bromine or iodine atom,by a trifluoromethyl, C₁₋₄ -alkoxy, C₁₋₄ -alkylsulphenyl, C₁₋₄-alkylsulphinyl, C₁₋₄ -alkylsulphonyl, nitro, amino, acetylamino,benzoylamino or methanesulphonylamino group, or a C₃₋₆ -cycloalkylenegroup, C represents an ethylene group optionally substituted by ahydroxy group, a methylenecarbonyl group linked to the group B via thecarbonyl group, or a phenylene group which may be substituted by one ortwo C₁₋₄ -alkyl groups, by a fluorine, chlorine, bromine or iodine atom,by a trifiuoromethyl, C₁₋₄ -alkoxy, C₁₋₄ -alkylsulphenyl, C₁₋₄-alkylsulphinyl, C₁₋₄ -alkylsulphonyl, nitro, amino, acetylamino,benzoylamino or methanesulphonylamino group, the other of the groupsR_(a) or R_(b) represents a group of formula

    F-E-D-

wherein D represents a C₁₋₄ -alkylene group, a phenylene group which maybe substituted by one or two C₁₋₄ -alkyl groups, by a fluorine,chlorine, bromine or iodine atom, by a trifiuoromethyl, C₁₋₄ -alkoxy,C₁₋₄ -alkylsulphenyl, C₁₋₄ -alkylsulphinyl, C₁₋₄ -alkylsulphonyl,carboxymethoxy, methoxycarbonylmethoxy, nitro, amino, acetylamino,benzoylamino or methanesulphonylamino group, a cyclohexylene groupoptionally substituted by one or two methyl groups, or a1,4-piperidinylene group, which is linked via the 1-position to theoptinally substituted C₁₋₄ -alkylene group of E with the proviso thatthe nitrogen atom of the 1,4-piperidinylene group is separated by atleast 2 carbon atoms from a heteroatom of the optinally substituted C₁₋₄-alkylene group of E; E represents a bond, a C₁₋₄ -alkylene groupoptionally substituted by one or two methyl groups or by a hydroxy,methoxy, amino, methylamino, dimethylamino, dibenzylamino, carboxymethylor methoxycarbonylmethyl group, a C₂₋₃ -alkenylene group, a phenylenegroup which may be substituted by one or two C₁₋₄ -alkyl groups, by afluorine, chlorine, bromine or iodine atom, by a trifiuoromethyl or C₁₋₄-alkoxy group, or a C₁₋₂ -alkylene group linked to group D by the groupW', wherein W' represents an oxygen or sulphur atom, a sulphinyl,sulphonyl, --NH--, --N(C₁₋₄ -alkyl)-, --N(COC₁₋₄ -alkyl)-, --N(SO₂ C₁₋₄-alkyl)-, aminocarbonyl or carbonylamino group; and F represents acarbonyl group substituted by a hydroxy group, by a C₁₋₆ -alkoxy groupor by a phenylalkoxy group having 1 or 2 carbon atoms in the alkoxypart, wherein if A represents an amino or aminoalkyl group optionallybenzyloxycarbonylated at the nitrogen atom, the shortest distancebetween the nitrogen atom of this group and group F is at least 10bonds; the tautomers, the stereoisomers, including the mixtures thereof,or the addition salts thereof.
 2. The imidazolidindione as recited inclaim 1, whereinY represents a --CR_(c) R_(d) CO-- group, whereinR_(c)represents a hydrogen atom, an C₁₋₃ -alkyl, trifiuoromethyl or phenylgroup, and Rd represents a hydrogen atom or an C₁₋₃ -alkyl group; one ofthe groups R_(a) or R_(b) represents a group of the formula

    A-B-C-

wherein A represents a straight-chained or branched C₁₋₄ -aminoalkylgroup, an amino or amidino group, wherein in each of the above-mentionedgroups, at one of the nitrogen atoms, a hydrogen atom may be replaced byan alkoxycarbonyl group having a total of 2 to 5 carbon atoms or by abenzyloxycarbonyl group; B represents a bond, a phenylene group whichmay be substituted by a fluorine, chlorine or bromine atom, by a methyl,trifluoromethyl or methoxy group, and C represents a phenylene groupwhich may be substituted by one or two methyl groups, by a fluorine,chlorine or bromine atom, by a methyl, trifluoromethyl or methoxy group,the other of the groups R_(a) or R_(b) represents a group of formula

    F-E-D-

wherein D represents a C₁₋₄ -alkylene group, a phenylene group which maybe substituted by a fluorine, chlorine or bromine atom, by a methyl,trifiuoromethyl or methoxy group, a cyclohexylene group, or a1,4-piperidinylene group, which is linked via the 1-position to theoptinally substituted methylene or ethylene group of E with the provisothat the nitrogen atom of the 1,4-piperidinylene group is separated byat least 2 carbon atoms from a heteroatom of the optinally substitutedmethylene or ethylene group of E; E represents a bond, a methylene orethylene group optionally substituted by one or two methyl groups or byan amino or dibenzylamino group, an ethenylene or phenylene group or amethylene group linked to group D by the group W', wherein W' representsan oxygen or sulphur atom, a sulphinyl, sulphonyl, --NH--, --N(C₁₋₂-Alkyl)-, --N(COC₁₋₂ -Alkyl)- or --N(SO₂ C₁₋₂ -Alkyl)- group; and Frepresents a carbonyl group substituted by a hydroxy group or by a C₁₋₆-alkoxy group, wherein if A represents an amino or aminoalkyl groupoptionally benzyloxycarbonylated at the nitrogen atom, the shortestdistance between the nitrogen atom of this group and group F is at least10 bonds; the tautomers, the stereoisomers, including the mixturesthereof, or the addition salts thereof.
 3. The imidazolidindione asrecited in claim 1, whereinY represents a --CR_(c) R_(d) CO-- group,whereinR_(c) represents a hydrogen, a methyl, ethyl, trifiuoromethyl orphenyl group, and R_(d) represents a hydrogen atom; one of the groupsR_(a) or R_(b) represents a group of formula

    A-B-C-

wherein A represents an aminomethyl or amidino group optionallysubstituted by an alkoxycarbonyl group with a total of 2 to 5 carbonatoms; B represents a bond or a 1,4-phenylene group; and C represents a1,4-phenylene group, the other of the groups R_(a) or R_(b) represents agroup of the formula

    F-E-D-

wherein D represents a C₁₋₄ -alkylene, 1,4-phenylene or1,4-cyclohexylene group, or a 1,4-piperidinylene group, which is linkedvia the 1-position to the ethylene group optionally substituted by oneor two methyl groups of E; E represents a bond, an ethylene groupoptionally substituted by one or two methyl groups, or an ethenylenegroup, or a methylene group linked by the group W' to a carbon atom ofthe group D, wherein W' represents an oxygen or sulphur atom, asulphinyl, sulphonyl, --NH-- or --N(CH₃)-- group; F represents acarbonyl group substituted by a hydroxy group or by a C₁₋₆ -alkoxygroup, wherein if A represents an aminomethyl group, the shortestdistance between the nitrogen atom of this group and group F is at least10 bonds; the tautomers, the stereoisomers, including the mixturesthereof, or the addition salts thereof.
 4. The imidazolidindione asrecited in claim 1, whereinY represents a --CR_(c) R_(d) CO-- group,whereinR_(c) represents a hydrogen, a methyl or ethyl group, and R_(d)represents a hydrogen atom; one of the groups R_(a) or R_(b) representsa group of formula

    A-B-C-

wherein A represents an amidino group optionally substituted by analkoxycarbonyl group with a total of 2 to 5 carbon atoms; B represents abond; and C represents a 1,4-phenylene group, the other of the groupsR_(a) or R_(b) represents a group of the formula

    F-E-D-

wherein D represents a 1,4-phenylene group; E represents an ethylenegroup, and F represents a carbonyl group substituted by a hydroxy groupor by a C₁₋₄ -alkoxy group; the tautomers, the stereoisomers, includingthe mixtures thereof, or the addition salts thereof. 5.1-(4-amidino-phenyl)-3-[4-(2-carboxy-ethyl)-phenyl]-imidazolidin-2,4-dione,or the addition salts thereof.